Adjustable connector, improved fluid flow and reduced clotting risk

ABSTRACT

Methods and systems for determining the concentration of one or more analytes from a sample such as blood or plasma are described. The systems described herein can be configured to withdraw a sample from a source of fluid, direct a first portion of the withdrawn sample to an analyte monitoring system and return a second portion of the sample. The analyte monitoring system can be connected to the fluid source via a connector that is configured to improve fluid flow and reduce blood clotting risk. These goals can be accomplished, for example, by employing coatings in or on a connector, positioning a resilient substance at or near the junction, by reducing dead space volume, by using resiliency to improve fit, by extending a portion of one connector to better mate with a portion of another connector, etc.

This application claims benefit under 35 U.S.C. §119(e) of U.S.Provisional Application No. 61/330,812, titled “Adjustable Connector andDead Space Reduction,” filed on May 3, 2010; this application is also acontinuation-in-part of, and claims benefit under 35 U.S.C. §120 of U.S.application Ser. No. 12/804,336, titled “Adjustable Connector and DeadSpace Reduction,” filed on Jul. 20, 2010, which in turn claims benefitunder 35 U.S.C. §119(e) of U.S. Provisional Application No. 61/227,040,titled “Analyte Detection System with a Flow Director,” filed on Jul.20, 2009. The entire disclosure of each of the above-identifiedapplications is incorporated by reference herein and made part of thisspecification.

This application also incorporates by reference herein in its entiretythe disclosure of U.S. patent application Ser. No. 12/122,009, titled“Low-Volume Fittings,” filed on May 16, 2008, which published as U.S.Publication No. 2008/0284167 on Nov. 20, 2008. This application alsoincorporates by reference herein in its entirety the disclosure of U.S.patent application Ser. No. 12/123,422, titled “Fluid Injection andSafety System,” filed on May 19, 2008, which published as U.S.Publication No. 2009/0036764 on Feb. 5, 2009.

BACKGROUND

1. Field

Some embodiments of the disclosure relate generally to methods anddevices for determining a concentration of an analyte in a sample, suchas an analyte in a sample of bodily fluid, as well as methods anddevices which can be used to support the making of such determinations.Various embodiments of the disclosure also relate to patient connectorsthat are configured to prevent or substantially reduce separated flow offluids. In various embodiments, the patient connector can generallyprevent accumulation of fluid during a flushing operation.

2. Description of Related Art

It is advantageous to measure the levels of certain analytes, such asglucose, in a bodily fluid, such as blood. This can be done, forexample, in a hospital or clinical setting when there is a risk that thelevels of certain analytes may move outside a desired range, which inturn can jeopardize the health of a patient. Systems for analytemonitoring in a hospital or clinical setting may suffer from variousdrawbacks. For example, fluid flow in the tubes and channels of systemscan occur in a non-laminar manner such that fluid is separated orbecomes stagnant in some places and turbulent in others. Thesediscontinuities can lead to fluid accumulation or clogging of tubes andpatient connectors. Systems and methods described herein can mitigateand/or overcome these drawbacks, both in the context of fluidconnections for analyte monitors and for fluid connections and flowpaths in other contexts.

SUMMARY

Example embodiments described herein have several features, no singleone of which is indispensible or solely responsible for their desirableattributes. Without limiting the scope of the claims, some of theadvantageous features will now be summarized.

Various embodiments disclosed herein can comprise a first inlet/outlet,a second inlet/outlet configured to connect to a mating connector, afluid path between the first inlet/outlet and the second inlet/outletwhich allows bidirectional fluid flow, an adjustable tip on the secondinlet/outlet configured to adjustably accommodate and firmly abut themating connector such that the fluid path in the accommodating connectorcommunicates immediately with a corresponding fluid path in the matingconnector and dead space between the fluid path and the correspondingfluid path is reduced, and a coating designed to improve fluid flow andreduce blood clotting which is applied to an inner portion of the fluidpath and therefore positioned for contact with the fluid. The coatingcan be applied to a surface near the interface between the secondinlet/outlet and the mating connector. The coating may be a drug-elutingcoating, a heparin coating, or a lubricious coating. The coating may beapplied to all portions of the accommodating connector that may comeinto contact with fluid in the fluid path. The accommodating connectorcan also have a sealing mass positioned near the interface of the secondinlet/outlet and the mating connector, which is designed to reduce deadspace at the connection. If the accommodating connector has such asealing mass, the coating may be applied to the mass. The sealing masscan have a shape configured to generally approximates the shape of anopening in the mating connector even when the accommodating connector isnot mating with the mating connector. The sealing mass can have afrustoconical shape. The sealing mass can be made of a resilient orcompressible material, or it can be made of silicone.

In some embodiments, an accommodating connector is described whichcomprises a first inlet/outlet; a second inlet/outlet configured toconnect to a mating connector; a fluid path between the firstinlet/outlet and the second inlet/outlet; an adjustable tip on thesecond inlet/outlet configured to adjustably accommodate and firmly abuta mating connector such that a passage from the accommodating connectorcommunicates immediately with a corresponding fluid path in the matingconnector and dead space between the fluid path and the correspondingfluid path is reduced; and a coating designed to improve fluid flow andreduce blood clotting which is applied to at least a portion of thefluid path. The fluid path in the connector can be a tube, and thecoating can be applied to a portion of the inner walls of this tube. Thecoating can be applied to a surface that is near the interface betweenthe second inlet/outlet and the mating connector. The coating can be adrug-eluting coating, a heparin coating, or a lubricious coating. Thecoating may be applied to all portions of the accommodating connectorthat may come into contact with fluid in the fluid path.

In some embodiments, an accommodating connector is described whichcomprises a first inlet/outlet; a second inlet/outlet configured toconnect to a mating connector; a fluid path between the firstinlet/outlet and the second inlet/outlet; an adjustable tip on thesecond inlet/outlet configured to adjustably accommodate and firmly abuta mating connector such that a passage from the accommodating connectorcommunicates immediately with a corresponding fluid path in the matingconnector and dead space between the fluid path and the correspondingfluid path is reduced; and a sealing mass that is positioned at or nearan interface between the second inlet/outlet and the mating connectorand that has a shape configured to correspond with a shape of the matingconnector when it is mating with the accommodating connector in order toreduce dead space at the interface between the second inlet/outlet andthe mating connector. The sealing mass can have a shape configured togenerally approximate the shape of an opening in the mating connectoreven when the accommodating connector is not mating with the matingconnector. The sealing mass can have a frustoconical shape. The sealingmass can be made of a resilient or compressible material, or it can bemade of silicone. The sealing mass may be able to form a fluid-tightseal around the fluid path when the accommodating connector is attachedto a mating connector. The mating connector may be a standard connector.The mating connector may be a standard female connector. The sealingmass may have a radially symmetric shape, in order to create a betterseal with the mating connector. The connector can have a coatingdesigned to improve fluid flow and reduce blood clotting applied to aportion of the fluid path. This coating may also be applied to a portionof the sealing mass.

In some embodiments, an accommodating connector is described whichcomprises a first inlet/outlet; a second inlet/outlet configured toconnect to a mating connector such that the second inlet/outletprotrudes from the accommodating connector in order to set the secondinlet/outlet near an inner portion of the mating connector; a fluid pathbetween the first inlet/outlet and the second inlet/outlet; a coatingdesigned to improve fluid flow and reduce blood clotting which isapplied to at least a portion of the fluid path; and a sealing mass thatis positioned at or near an interface between the second inlet/outletand the mating connector and that has a shape configured to correspondwith a shape of the mating connector when it is mating with theaccommodating connector in order to reduce dead space at the interfacebetween the second inlet/outlet and the mating connector. The sealingmass can have a shape configured to generally approximate the shape ofan opening in the mating connector even when the accommodating connectoris not mating with the mating connector. The sealing mass can have afrustoconical shape. The sealing mass can be made of a resilient orcompressible material, or it can be made of silicone. The coating may beapplied to the sealing mass. The coating can be applied to a surfacethat is near the interface between the second inlet/outlet and themating connector. The coating can be a drug-eluting coating, a heparincoating, or a lubricious coating.

In some embodiments, a patient connector is described which comprises afirst inlet/outlet, a second inlet/outlet configured to connect to astandard mating connector, a fluid path between the first inlet/outletand the second inlet/outlet, and a sealing mass that is positioned at ornear an interface between the second inlet/outlet and the standardmating connector and that has a shape configured to correspond with ashape of the standard mating connector when it is mating with thepatient connector in order to form at least a partial seal and to reducedead space at the interface between the second inlet/outlet and thestandard mating connector. The standard mating connector may be astandard female connector. The sealing mass may be made from a resilientor compressible material, or may be made from silicone. The patientconnector may have a coating designed to improve fluid flow and reduceblood clotting which is applied to at least a portion of the fluid path.This coating may be applied to at least a portion of the sealing mass.

In some embodiments, a patient connector is described which comprises afirst inlet/outlet, a second inlet/outlet configured to connect to amating connector, a fluid path between the first inlet/outlet and thesecond inlet/outlet that is designed to minimize turbulence in the fluidpath in order to improve fluid flow and reduce blood clotting, and alubricious coating which is applied to at least a portion of the fluidpath that may come into contact with a fluid flow at least partlycomprised of blood, where the lubricious coating is designed to reducefriction and improve fluid flow and reduce turbulence and bloodclotting. The lubricious coating may be applied to all portions of thepatient connector that may come into contact with fluid in the fluidpath.

In some embodiments, a system for extending the length of time a medicaldevice connector can be used for repeated blood withdrawal is described.The system comprises a fluid draw apparatus having a fluid passagewayconfigured for blood withdrawal and fluid infusion through the samepassageway, and a medical device connector configured to connect thepassageway of the fluid draw apparatus to a patient catheter for accessto a blood vessel. The medical device connector comprises: a housingconfigured to firmly connect to the patient catheter, and a tube havinga tube passageway and a tip, the tube generally positioned within thehousing and configured to firmly connect and align its tube passagewaywith the fluid passageway. The medical connector further comprises oneor more of the following: with the fluid passageway firmly connected toone end of the tube, the tube is configured to resiliently move withrespect to the housing such that the tube is urged toward the patientcatheter to resiliently and forcefully abut that catheter, minimizeleaks or other dead space, and align an inner passageway of thatcatheter with the tube passageway when the housing is firmly connectedto the patient catheter, thereby minimizing clot formation; the tube isconfigured to protrude toward the patient catheter and comprises asealing mass adhered to or formed as part of the tip, the sealing massgenerally surrounding the tube and configured to resiliently andforcefully abut the catheter and minimize leaks or other dead space whenthe housing is firmly connected to the patient catheter, therebyminimizing clot formation; and a lubricious coating in and/or around thetube passageway, the coating configured to lubricate blood-contactingsurfaces to reduce friction and turbulence, thereby minimizing clotformation. The medical device connector is thereby configured to allowat least 12 hours of repeated blood draws into the fluid passagewaywithout clot formation.

In some embodiments, a connector configured for use with a bloodwithdrawal system is described. The connector comprises: a housingconfigured to firmly connect to a vessel access device; and a tubehaving a tube passageway and a tip, the tube generally positioned withinthe housing and configured to firmly connect and align its tubepassageway with a fluid passageway of the blood withdrawal system. Theconnector is further configured for at least 12 hours of periodic,repeated blood withdrawal using at least one of the following: with thefluid passageway firmly connected to one end of the tube, the tube isconfigured to resiliently move with respect to the housing such that thetube is urged toward the vessel access device to resiliently andforcefully abut that vessel access device, minimize leaks or other deadspace, and align an inner passageway of that vessel access device withthe tube passageway when the housing is firmly connected to the vesselaccess device, thereby minimizing clot formation; the tube is configuredto protrude toward the vessel access device and comprises a sealing massadhered to or formed as part of the tip, the sealing mass generallysurrounding the tube and configured to resiliently and forcefully abutthe vessel access device and minimize leaks or other dead space when thehousing is firmly connected to the vessel access device, therebyminimizing clot formation; and a lubricious coating in and/or around thetube passageway, the coating configured to lubricate blood-contactingsurfaces to reduce friction and turbulence, thereby minimizing clotformation.

In some embodiments, a connector configured to resist clot formation forat least 12 hours of periodic blood withdrawals is described. Theconnector resists clot formation for this time by incorporating at leastone of the following three structures: a protruding inner tubeconfigured to resiliently press against a patient catheter to provide acontiguous blood flow path and minimize gaps at a junction between thepatient catheter and the protruding inner tube; a protruding inner tubecomprising a sealing mass adhered to or formed as part of the tube, thesealing mass generally surrounding the tube and configured toresiliently and forcefully abut the patient catheter and minimize gapssurrounding the junction between the patient catheter and the protrudinginner tube when the connector is connected to the patient catheter; anda protruding inner tube having a lubricious coating in and/or around thetube, the coating configured to lubricate blood-contacting surfaces toreduce friction and turbulence, thereby minimizing clot formation.

Various embodiments disclosed herein can comprise an analyte monitoringsystem further comprising a fluidic system in fluid communication with asource of bodily fluid, the fluidic system being configured to obtain asample of bodily fluid from the source; a spectroscopic sample cell influid communication with the fluidic system and configured to receivethe sample of bodily fluid; an analyte detection system coupled to thespectroscopic sample cell through a transparent window, the analytedetection system spectroscopically analyzing the sample of bodily fluidor a component of the sample of bodily fluid; and a fluid infusionsystem. In various embodiments, the analyte detection system isconfigured to estimate the concentration of an analyte in the sample ofthe bodily fluid or a component of the sample of the bodily fluid. Invarious embodiments, the fluidic system is fluidically connected to thesource of bodily fluid through a patient connector which includes aspring loaded self adjusting extender tube and is configured to providea continuous flow path.

In some embodiments, a system for eliminating dead space and improvingfluid flow through medical connectors is described. The system comprisesan outer portion comprising at least one standard-facing end (e.g. aLuer male or female connector); an inner portion comprising an extendedflow passageway; and an actuating member that is situated between theouter and the inner portion and configured to move the inner portiontoward or away from the outer portion thereby causing the extended flowpassageway to approach an inner portion of any of a variety of standardconnectors (e.g. standard Luer connectors) having different depths.

In some embodiments an extendable medical connector for reducing deadspace and improving fluid flow is described. The connector comprises astandard-facing end (e.g. a Luer male or female connector) comprising astandard-facing outer portion; and a standard-facing inner portioncomprising an extended flow passageway. The connector further includesan opposite end comprising an opposite outer portion comprising a firstpushing surface; and a receiving opening configured to receive a regularflow passageway. In various embodiments, the standard-facing outerportion and the opposite outer portion together can comprising an outerhousing. In various embodiments, the connector may include a secondpushing surface facing the first pushing surface. In variousembodiments, the extended flow passageway configured to connect to theregular flow passageway to form a combined flow passageway configured tomove with the second pushing surface. The connector may also include aforce exerting member is situated between the first and second pushingsurfaces and configured to simultaneously exert a force against both ofthese pushing surfaces to thereby urge the first pushing surface (alongwith the outer housing) away from the second pushing surface (along withthe combined inner portion), thereby causing the extended flowpassageway to approach—and the inner portion of the standard-facing endto more firmly seat against—an inner portion of any of a variety ofstandard connectors having different depths.

In some embodiments, a penetrating connector configured to be positionedalong a fluid line between a medical device and a source of body fluidto allow fluid flow while reducing leaks is described. The connector caninclude first and second openings at either end of the connector, theopenings configured to allow fluid communication—through theconnector—between the medical device and the source of body fluid; andcooperate with openings of other connecting devices to assist in formingmating complexes at either side end of the connector, at least one ofthe mating complexes having an enlarged space. The connector can alsoinclude an extender tube having a first cross-sectional width, theextender tube configured to convey the fluid along a fluid pathway thatextends at least part of the way between the first and second openings;penetrate through at least one of the mating complexes while bypassingthe enlarged space, which has a cross sectional width that is wider thanthe first cross-sectional width; confine fluid within its walls toprevent the fluid from flowing out into the enlarged space of the matingcomplex; and abut an opening of one of the other connecting devices suchthat fluid flows directly between the extender tube and the opening ofthe other connecting device. The connector can further include aforce-exerting structure that uses a resilient property to improve aseal where the extender tube abuts the opening of the other connectingdevice.

In various embodiments, an accommodating connector configured to reduceleaks and improve fluid flow between a medical device and a source ofbody fluid, the accommodating connector comprising a first inlet/outlet;a second inlet/outlet; and a force-exerting structure having astiffness. The accommodating connector is configured to connect to amating connector that is attached to a source of bodily fluid; and theforce-exerting structure is configured to exert a force on an innerportion of the mating connector in a contact region and firmly seat thefirst or second inlet/outlet against the inner portion of the matingconnector such that a dead space between the first or secondinlet/outlet and the inner portion of the mating connector is reduced.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

The following drawings and the associated descriptions are provided toillustrate embodiments of the present disclosure and do not limit thescope of the claims.

FIG. 1 shows an embodiment of an apparatus for withdrawing and analyzingfluid samples.

FIG. 2 illustrates how various other devices can be supported on or nearan embodiment of apparatus illustrated in FIG. 1.

FIG. 3 illustrates an embodiment of the apparatus in FIG. 1 configuredto be connected to a patient.

FIG. 3A illustrates an embodiment of the apparatus in FIG. 1 that is notconfigured to be connected to a patient but which receives a fluidsample from an extracorporeal fluid container such as, for example, atest tube. This embodiment of the apparatus advantageously provides invitro analysis of a fluid sample.

FIG. 4 is a block diagram of an embodiment of a system for withdrawingand analyzing fluid samples.

FIG. 5 schematically illustrates an embodiment of a fluid system thatcan be part of a system for withdrawing and analyzing fluid samples.

FIG. 6 schematically illustrates another embodiment of a fluid systemthat can be part of a system for withdrawing and analyzing fluidsamples.

FIG. 7 is an oblique schematic depiction of an embodiment of amonitoring device.

FIG. 8 shows a cut-away side view of an embodiment of a monitoringdevice.

FIG. 9 shows a cut-away perspective view of an embodiment of amonitoring device.

FIG. 10 illustrates an embodiment of a removable cartridge that caninterface with a monitoring device.

FIG. 11 illustrates an embodiment of a fluid routing card that can bepart of the removable cartridge of FIG. 10.

FIG. 12 illustrates how non-disposable actuators can interface with thefluid routing card of FIG. 11.

FIG. 13 illustrates a modular pump actuator connected to a syringehousing that can form a portion of a removable cartridge.

FIG. 14 shows a rear perspective view of internal scaffolding and somepinch valve pump bodies.

FIG. 15 shows an underneath perspective view of a sample cell holderattached to a centrifuge interface, with a view of an interface with asample injector.

FIG. 16 shows a plan view of a sample cell holder with hidden and/ornon-surface portions illustrated using dashed lines.

FIG. 17 shows a top perspective view of the centrifuge interfaceconnected to the sample holder.

FIG. 18 shows a perspective view of an example optical system.

FIG. 19 shows a filter wheel that can be part of the optical system ofFIG. 18.

FIG. 20 schematically illustrates an embodiment of an optical systemthat comprises a spectroscopic analyzer adapted to measure spectra of afluid sample.

FIG. 21 is a flowchart that schematically illustrates an embodiment of amethod for estimating the concentration of an analyte in the presence ofinterferents.

FIG. 22 is a flowchart that schematically illustrates an embodiment of amethod for performing a statistical comparison of the absorptionspectrum of a sample with the spectrum of a sample population andcombinations of individual library interferent spectra.

FIG. 23 is a flowchart that schematically illustrates an exampleembodiment of a method for estimating analyte concentration in thepresence of the possible interferents.

FIGS. 24 and 25 schematically illustrate the visual appearance ofembodiments of a user interface for a system for withdrawing andanalyzing fluid samples.

FIG. 26 schematically depicts various components and/or aspects of apatient monitoring system and the relationships among the componentsand/or aspects.

FIG. 27 is a flowchart that schematically illustrates an embodiment of amethod of providing glycemic control.

FIG. 28A illustrates a cross-section of a male Luer hub connector.

FIG. 28B illustrates a cross-section of a male Luer extended to take upvolume in a catheter Luer.

FIG. 29A-29D illustrates various embodiments of Luer connectors.

FIG. 30A schematically illustrates a patient connector including a flowdirector.

FIG. 30B schematically illustrates another embodiment of a patientconnector assembly including a flow director.

FIGS. 30C1-30C3 schematically illustrate different views of a patientconnector assembly including a flow director.

FIGS. 30D1-30D6 schematically illustrate different views of a patientconnector assembly.

FIGS. 30E1-30E4 schematically illustrate different views of a flowdirector.

FIG. 31 schematically illustrates a method of bonding the flow directorto a male Luer patient connector.

FIG. 32A illustrates a flow pattern in an embodiment of a patientconnector. FIG. 32A-1 is a color version of FIG. 32A.

FIG. 32B illustrates a flow pattern in an embodiment of a patientconnector including a tapered region. FIG. 32B-1 is a color version ofFIG. 32B.

FIG. 32C-32E illustrates a flow pattern in various embodiments of apatient connector including a flow director. FIGS. 32C-1-32E-1 are colorversions of FIGS. 32C-32E.

FIG. 33A illustrates an embodiment of a patient connector including aflow director.

FIGS. 33B-33C illustrate the embodiment of a patient connector shown inFIG. 33A during use and after use.

FIG. 34A illustrates an experimental setup used to test the flowdirecting ability of various embodiments of a patient connectorincluding a flow director.

FIG. 34B shows an internal view of an embodiment of the patientconnector used in the setup of FIG. 34A.

FIG. 35 shows an experimental setup to test the flow directing abilityof the embodiment of a patient connector including a flow director.

FIG. 36A illustrates an embodiment of a self-adjusting patientconnector.

FIG. 36B illustrates an exploded view of the self-adjusting patientconnector disclosed in FIG. 36A.

FIGS. 36C-36J are generalized illustrations of self-adjustingconnectors.

FIGS. 36K-36L are generalized illustrations of a sealing mass.

FIGS. 36M-36N are illustrations of self-adjusting connectors that have asealing mass.

FIGS. 37A-37H illustrate a self-adjusting patient connector connected tocentral venous catheters and peripherally inserted central cathetershaving different diameters.

FIGS. 38A-38C and 39 illustrate the use of embodiments of aself-adjusting patient connector in a study to test for performance andcompatibility.

These and other features will now be described with reference to thedrawings summarized above. The drawings and the associated descriptionsare provided to illustrate embodiments and not to limit the scope of thedisclosure or claims. Throughout the drawings, reference numbers may bereused to indicate correspondence between referenced elements. Inaddition, where applicable, the first one or two digits of a referencenumeral for an element can frequently indicate the figure number inwhich the element first appears.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Although certain preferred embodiments and examples are disclosed below,inventive subject matter extends beyond the specifically disclosedembodiments to other alternative embodiments and/or uses and tomodifications and equivalents thereof. Thus, the scope of the claimsappended hereto is not limited by any of the particular embodimentsdescribed below. For example, in any method or process disclosed herein,the acts or operations of the method or process may be performed in anysuitable sequence and are not necessarily limited to any particulardisclosed sequence. Various operations may be described as multiplediscrete operations in turn, in a manner that may be helpful inunderstanding certain embodiments; however, the order of descriptionshould not be construed to imply that these operations are orderdependent. Additionally, the structures, systems, and/or devicesdescribed herein may be embodied as integrated components or as separatecomponents. For purposes of comparing various embodiments, certainaspects and advantages of these embodiments are described. Notnecessarily all such aspects or advantages are achieved by anyparticular embodiment. Thus, for example, various embodiments may becarried out in a manner that achieves or optimizes one advantage orgroup of advantages as taught herein without necessarily achieving otheraspects or advantages as may also be taught or suggested herein.

The systems and methods discussed herein can be used anywhere,including, for example, in laboratories, hospitals, healthcarefacilities, intensive care units (ICUs), or residences. Moreover, thesystems and methods discussed herein can be used for invasivetechniques, as well as non-invasive techniques or techniques that do notinvolve a body or a patient such as, for example, in vitro techniques.

Analyte Monitoring Apparatus

FIG. 1 shows an embodiment of an apparatus 100 for withdrawing andanalyzing fluid samples. The apparatus 100 includes a monitoring device102. In some embodiments, the monitoring device 102 can be anOPTISCANNER™ monitor available from OptiScan Biomedical Corporation ofHayward, Calif. In some embodiments, the device 102 can measure one ormore physiological parameters, such as the concentration of one or moresubstance(s) in a sample fluid. The sample fluid can be, for example,whole blood from a patient 302 (see, e.g., FIG. 3) and/or a component ofwhole blood such as, e.g., blood plasma. In some embodiments, the device100 can also deliver an infusion fluid to a patient.

In the illustrated embodiment, the monitoring device 102 includes adisplay 104 such as, for example, a touch-sensitive liquid crystaldisplay. The display 104 can provide an interface that includes alerts,indicators, charts, and/or soft buttons. The device 102 also can includeone or more inputs and/or outputs 106 that provide connectivity and/orpermit user interactivity.

In the embodiment shown in FIG. 1, the device 102 is mounted on a stand108. The stand 108 may comprise a cart such as, for example, a wheeledcart 130 as shown in FIG. 1. In some embodiments, the stand 108 isconfigured to roll on a wheeled pedestal 240 (shown in FIG. 2). Thestand 108 advantageously can be easily moved and includes one or morepoles 110 and/or hooks 112. The poles 110 and hooks 112 can beconfigured to accommodate other medical devices and/or implements,including, for example, infusion pumps, saline bags, arterial pressuresensors, other monitors and medical devices, and so forth. Some standsor carts may become unstable if intravenous (IV) bags, IV pumps, andother medical devices are hung too high on the stand or cart. In someembodiments, the apparatus 100 can be configured to have a low center ofgravity, which may overcome possible instability. For example, the stand108 can be weighted at the bottom to at least partially offset theweight of IV bags, IV pumps and medical devices that may be attached tothe hooks 112 that are placed above the monitoring device 102. Addingweight toward the bottom (e.g., near the wheels) may help prevent theapparatus 100 from tipping over.

In some embodiments, the apparatus 100 includes the cart 130, which hasan upper shelf 131 on which the monitoring device 102 may be placed (orattached) and a bottom shelf 132 on which a battery 134 may be placed(or attached). The battery 134 may be used as a main or backup powersupply for the monitoring device 102 (which may additionally oralternatively accept electrical power from a wall socket). Two or morebatteries are used in certain embodiments. The apparatus 100 may beconfigured so that the upper and lower shelves 131, 132 are close toground level, and the battery provides counterweight. Other types ofcounterweights may be used. For example, in some embodiments, portionsof the cart 130 near the floor (e.g., a lower shelf) are weighted,formed from a substantial quantity of material (e.g., thick sheets ofmetal), and/or formed from a relatively high-density metal (e.g., lead).In some embodiments the bottom shelf 132 is approximately 6 inches to 1foot above ground level, and the upper shelf 131 is approximately 2 feetto 4 feet above ground level. In some embodiments the upper shelf 131may be configured to support approximately 40 pounds (lbs), and thebottom shelf 132 may be configured to support approximately 20 lbs. Onepossible advantage of embodiments having such a configuration is that IVpumps, bags containing saline, blood and/or drugs, and other medicalequipment weighing approximately 60 lbs, collectively, can be hung onthe hooks 112 above the shelves without making the apparatus 100unstable. The apparatus 100 may be moved by applying a horizontal forceon the apparatus 100, for example, by pushing and/or pulling the poles110. In many cases, a user may exert force on an upper portion of theapparatus 100, for example, close to shoulder-height. Bycounterbalancing the weight as described above, the apparatus 100 may bemoved in a reasonably stable manner.

In the illustrated embodiment, the cart 130 includes the bottom shelf132 and an intermediate shelf 133, which are enclosed on three sides bywalls and on a fourth side by a door 135. The door 135 can be opened (asshown in FIG. 1) to provide access to the shelves 132, 133. In otherembodiments, the fourth side is not enclosed (e.g., the door 135 is notused). Many cart variations are possible. In some embodiments thebattery 134 can be placed on the bottom shelf 134 or the intermediateshelf 133.

FIG. 2 illustrates how various other devices can be supported on or nearthe apparatus 100 illustrated in FIG. 1. For example, the poles 110 ofthe stand 108 can be configured (e.g., of sufficient size and strength)to accommodate multiple devices 202, 204, 206. In some embodiments, oneor more COLLEAGUE® volumetric infusion pumps available from BaxterInternational Inc. of Deerfield, Ill. can be accommodated. In someembodiments, one or more Alaris® PC units available from CardinalHealth, Inc. of Dublin, Ohio can be accommodated. Furthermore, variousother medical devices (including the two examples mentioned here), canbe integrated with the disclosed monitoring device 102 such thatmultiple devices function in concert for the benefit of one or multiplepatients without the devices interfering with each other.

FIG. 3 illustrates the apparatus 100.of FIG. 1 as it can be connected toa patient 302. The monitoring device 102 can be used to determine theconcentration of one or more substances in a sample fluid. The samplefluid can come can come from the patient 302, as illustrated in FIG. 3,or the sample fluid can come from a fluid container, as illustrated inFIG. 3A. In some preferred embodiments, the sample fluid is whole blood.

In some embodiments (see, e.g., FIG. 3), the monitoring device 102 canalso deliver an infusion fluid to the patient 302. An infusion fluidcontainer 304 (e.g., a saline bag), which can contain infusion fluid(e.g., saline and/or medication), can be supported by the hook 112. Themonitoring device 102 can be in fluid communication with both thecontainer 304 and the sample fluid source (e.g., the patient 302),through tubes 306. The infusion fluid can comprise any combination offluids and/or chemicals. Some advantageous examples include (but are notlimited to): water, saline, dextrose, lactated Ringer's solution, drugs,and insulin.

The example monitoring device 102 schematically illustrated in FIG. 3allows the infusion fluid to pass to the patient 302 and/or uses theinfusion fluid itself (e.g., as a flushing fluid or a standard withknown optical properties, as discussed further below). In someembodiments, the monitoring device 102 may not employ infusion fluid.The monitoring device 102 may thus draw samples without delivering anyadditional fluid to the patient 302. The monitoring device 102 caninclude, but is not limited to, fluid handling and analysis apparatuses,connectors, passageways, catheters, tubing, fluid control elements,valves, pumps, fluid sensors, pressure sensors, temperature sensors,hematocrit sensors, hemoglobin sensors, colorimetric sensors, gas (e.g.,“bubble”) sensors, fluid conditioning elements, gas injectors, gasfilters, blood plasma separators, and/or communication devices (e.g.,wireless devices) to permit the transfer of information within themonitoring device 102 or between the monitoring device 102 and anetwork.

In some embodiments, the apparatus 100 is not connected to a patient andmay receive fluid samples from a container such as a decanter, flask,beaker, tube, cartridge, test strip, etc., or any other extracorporealfluid source. The container may include a biological fluid sample suchas, e.g., a body fluid sample. For example, FIG. 3A schematicallyillustrates an embodiment of the monitoring device 102 that isconfigured to receive a fluid sample from one or more test tubes 350.This embodiment of the monitoring device 102 is configured to perform invitro analysis of a fluid (or a fluid component) in the test tube 350.The test tube 350 may comprise a tube, vial, bottle, or, other suitablecontainer or vessel. The test tube 350 may include an opening disposedat one end of the tube through which the fluid sample may be added priorto delivery of the test tube to the monitoring device 102. In someembodiments, the test tubes 350 may also include a cover adapted to sealthe opening of the tube. The cover may include an aperture configured topermit a tube, nozzle, needle, pipette, or syringe to dispense the fluidsample into the test tube 350. The test tubes 350 may comprise amaterial such as, for example, glass, polyethylene, or polymericcompounds. In various embodiments, the test tubes 350 may be re-usableunits or may be disposable, single-use units. In certain embodiments,the test tubes 350 may comprise commercially available lowpressure/vacuum sample bottles, test bottles, or test tubes.

In the embodiment shown in FIG. 3A, the monitoring device 102 comprisesa fluid delivery system 360 configured to receive a container (e.g., thetest tube 350) containing a fluid sample and deliver the fluid sample toa fluid handling system (such as, e.g., fluid handling system 404described below). In some embodiments, the fluid handling systemdelivers a portion of the fluid sample to an analyte detection systemfor in vitro measurement of one or more physiological parameters (e.g.,an analyte concentration). Prior to measurement, the fluid handlingsystem may, in some embodiments, separate the fluid sample intocomponents, and a measurement may be performed on one or more of thecomponents. For example, the fluid sample in the test tube 350 maycomprise whole blood, and the fluid handling system may separate bloodplasma from the sample (e.g., by filtering and/or centrifuging).

In the embodiment illustrated in FIG. 3A, the fluid delivery system 360comprises a carousel 362 having one or more openings 364 adapted toreceive the test tube 350. The carousel 362 may comprise one, two, four,six, twelve, or more openings 364. In the illustrated embodiment, thecarousel 362 is configured to rotate around a central axis or spindle366 so that a test tube 350 inserted into one of the openings 364 isdelivered to the monitoring device 102. In certain embodiments, thefluid handling system of the monitoring device 102 comprises a samplingprobe that is configured to collect a portion of the fluid sample fromthe test tube 350 (e.g., by suction or aspiration). The collectedportion may then be transported in the device 102 as further describedbelow (see, e.g., FIGS. 4-7). For example, in one embodiment suitablefor use with whole blood, the collected portion of the whole bloodsample is transported to a centrifuge for separation into blood plasma,a portion of the blood plasma is transported to an infrared spectroscopefor measurement of one or more analytes (e.g., glucose), and themeasured blood plasma is then transported to a waste container fordisposal.

In other embodiments of the apparatus 100 shown in FIG. 3A, the fluiddelivery system 360 may comprise a turntable, rack, or caddy adapted toreceive the test tube 350. In yet other embodiments, the monitoringdevice 102 may comprise an inlet port adapted to receive the test tube350. Additionally, in other embodiments, the fluid sample may bedelivered to the apparatus 100 using a test cartridge, a test strip, orother suitable container. Many variations are possible.

In some embodiments, one or more components of the apparatus 100 can belocated at another facility, room, or other suitable remote location.One or more components of the monitoring device 102 can communicate withone or more other components of the monitoring device 102 (or with otherdevices) by communication interface(s) such as, but not limited to,optical interfaces, electrical interfaces, and/or wireless interfaces.These interfaces can be part of a local network, interne, wirelessnetwork, or other suitable networks.

System Overview

FIG. 4 is a block diagram of a system 400 for sampling and analyzingfluid samples. The monitoring device 102 can comprise such a system. Thesystem 400 can include a fluid source 402 connected to a fluid-handlingsystem 404. The fluid-handling system 404 includes fluid passageways andother components that direct fluid samples. Samples can be withdrawnfrom the fluid source 402 and analyzed by an optical system 412. Thefluid-handling system 404 can be controlled by a fluid system controller405, and the optical system 412 can be controlled by an optical systemcontroller 413. The sampling and analysis system 400 can also include adisplay system 414 and an algorithm processor 416 that assist in fluidsample analysis and presentation of data.

In some embodiments, the sampling and analysis system 400 is a mobilepoint-of-care apparatus that monitors physiological parameters such as,for example, blood glucose concentration. Components within the system400 that may contact fluid and/or a patient, such as tubes andconnectors, can be coated with an antibacterial coating to reduce therisk of infection. Connectors between at least some components of thesystem 400 can include a self-sealing valve, such as a spring valve, inorder to reduce the risk of contact between port openings and fluids,and to guard against fluid escaping from the system. Other componentscan also be included in a system for sampling and analyzing fluid inaccordance with the described embodiments.

The sampling and analysis system 400 can include a fluid source 402 (ormore than one fluid source) that contain(s) fluid to be sampled. Thefluid-handling system 404 of the sampling and analysis system 400 isconnected to, and can draw fluid from, the fluid source 402. The fluidsource 402 can be, for example, a blood vessel such as a vein or anartery, a container such as a decanter, flask, beaker, tube, cartridge,test strip, etc., or any other corporeal or extracorporeal fluid source.For example, in some embodiments, the fluid source 402 may be a vein orartery in the patient 302 (see, e.g., FIG. 3). In other embodiments, thefluid source 402 may comprise an extracorporeal container 350 of fluiddelivered to the system 400 for analysis (see, e.g., FIG. 3B). The fluidto be sampled can be, for example, blood, plasma, interstitial fluid,lymphatic fluid, or another fluid. In some embodiments, more than onefluid source can be present, and more than one fluid and/or type offluid can be provided.

In some embodiments, the fluid-handling system 404 withdraws a sample offluid from the fluid source 402 for analysis, centrifuges at least aportion of the sample, and prepares at least a portion of the sample foranalysis by an optical sensor such as a spectrophotometer (which can bepart of an optical system 412, for example). These functions can becontrolled by a fluid system controller 405, which can also beintegrated into the fluid-handling system 404. The fluid systemcontroller 405 can also control the additional functions describedbelow. In some embodiments, the sample can be withdrawn continuously orsubstantially continuously at certain time intervals with a givenperiod. The time intervals at which the sample is withdrawn can beperiodic or aperiodic and range from approximately 1 minute toapproximately 15 minutes (e.g., the sample can be withdrawn at timeintervals of 1 minute, 5 minutes, 10 minutes or 15 minutes). In someembodiments, the sample can be withdrawn at discrete time intervals(e.g., once every 30 minutes, once every 45 minutes or once every hour).

The duration of time over which the sample of fluid is withdrawn,referred to as “draw period”, may be set to avoid clinical drawbacks,and/or it can be varied according to a health-care provider's wishes.For example, in some embodiments, fluid may be continuously withdrawninto the sampling and analysis system 400 over a draw period lastingapproximately 10 seconds to approximately 5 minutes.

In some embodiments, the amount of sample withdrawn from the fluidsource 402 can be small. For example, in some embodiments, the volume ofsample withdrawn from the fluid source can be between approximately 1.0ml and approximately 10.0 ml in a draw period (e.g. 2.0 ml-6.0 ml ofsample can be withdrawn in a draw period of approximately 1 minute). Insome embodiments, the amount of sample withdrawn can be in the range ofapproximately 20 ml/day to approximately 500 ml/day. In someembodiments, the amount of sample withdrawn can be outside this range.

In some embodiments, at least a portion of the sample is returned to thefluid source 402. At least some of the sample, such as portions of thesample that are mixed with other materials or portions that areotherwise altered during the sampling and analysis process, or portionsthat, for any reason, are not to be returned to the fluid source 402,can also be placed in a waste bladder (not shown in FIG. 4). The wastebladder can be integrated into the fluid-handling system 404 or suppliedby a user of the system 400. The fluid-handling system 404 can also beconnected to a saline source, a detergent source, and/or ananticoagulant source, each of which can be supplied by a user, attachedto the fluid-handling system 404 as additional fluid sources, and/orintegrated into the fluid-handling system 404.

Components of the fluid-handling system 404 can be modularized into oneor more non-disposable, disposable, and/or replaceable subsystems. Inthe embodiment shown in FIG. 4, components of the fluid-handling system404 are separated into a non-disposable subsystem 406, a firstdisposable subsystem 408, and a second disposable subsystem 410.

The non-disposable subsystem 406 can include components that, while theymay be replaceable or adjustable, do not generally require regularreplacement during the useful lifetime of the system 400. In someembodiments, the non-disposable subsystem 406 of the fluid-handlingsystem 404 includes one or more reusable valves and sensors. Forexample, the non-disposable subsystem 406 can include one or more valves(or non-disposable portions thereof), (e.g., pinch-valves, rotaryvalves, etc.), sensors (e.g., ultrasonic bubble sensors, non-contactpressure sensors, optical blood dilution sensors, etc). Thenon-disposable subsystem 406 can also include one or more pumps (ornon-disposable portions thereof). For example, some embodiments caninclude pumps available from Hospira. In some embodiments, thecomponents of the non-disposable subsystem 406 are not directly exposedto fluids and/or are not readily susceptible to contamination.

The first and second disposable subsystems 408, 410 can includecomponents that are regularly replaced under certain circumstances inorder to facilitate the operation of the system 400. For example, thefirst disposable subsystem 408 can be replaced after a certain period ofuse, such as a few days, has elapsed. Replacement may be necessary, forexample, when a bladder within the first disposable subsystem 408 isfilled to capacity. Such replacement may mitigate fluid systemperformance degradation associated with and/or contamination wear onsystem components.

In some embodiments, the first disposable subsystem 408 includescomponents that may contact fluids such as patient blood, saline,flushing solutions, anticoagulants, and/or detergent solutions. Forexample, the first disposable subsystem 408 can include one or moretubes, fittings, cleaner pouches and/or waste bladders. The componentsof the first disposable subsystem 408 can be sterilized in order todecrease the risk of infection and can be configured to be easilyreplaceable.

In some embodiments, the second disposable subsystem 410 can be designedto be replaced under certain circumstances. For example, the seconddisposable subsystem 410 can be replaced when the patient beingmonitored by the system 400 is changed. The components of the seconddisposable subsystem 410 may not need replacement at the same intervalsas the components of the first disposable subsystem 408. For example,the second disposable subsystem 410 can include a sample holder and/orat least some components of a centrifuge, components that may not becomefilled or quickly worn during operation of the system 400. Replacementof the second disposable subsystem 410 can decrease or eliminate therisk of transferring fluids from one patient to another during operationof the system 400, enhance the measurement performance of system 400,and/or reduce the risk of contamination or infection.

In some embodiments, the sample holder of the second disposablesubsystem 410 receives the sample obtained from the fluid source 402 viafluid passageways of the first disposable subsystem 408. The sampleholder is a container that can hold fluid for the centrifuge and caninclude a window to the sample for analysis by a spectrometer. In someembodiments, the sample holder includes windows that are made of amaterial that is substantially transparent to electromagnetic radiationin the mid-infrared range of the spectrum. For example, the sampleholder windows can be made of calcium fluoride.

An injector can provide a fluid connection between the first disposablesubsystem 408 and the sample holder of the second disposable subsystem410. In some embodiments, the injector can be removed from the sampleholder to allow for free spinning of the sample holder duringcentrifugation.

In some embodiments, the components of the sample are separated bycentrifuging for a period of time before measurements are performed bythe optical system 412. For example, a fluid sample (e.g., a bloodsample) can be centrifuged at a relatively high speed. The sample can bespun at a certain number of revolutions per minute (RPM) for a givenlength of time to separate blood plasma for spectral analysis. In someembodiments, the fluid sample is spun at about 7200 RPM. In someembodiments, the sample is spun at about 5000 RPM. In some embodiments,the fluid sample is spun at about 4500 RPM. In some embodiments, thefluid sample is spun at more than one rate for successive time periods.The length of time can be approximately 5 minutes. In some embodiments,the length of time is approximately 2 minutes. Separation of a sampleinto the components can permit measurement of solute (e.g., glucose)concentration in plasma, for example, without interference from otherblood components. This kind of post-separation measurement, (sometimesreferred to as a “direct measurement”) has advantages over a solutemeasurement taken from whole blood because the proportions of plasma toother components need not be known or estimated in order to infer plasmaglucose concentration. In some embodiments, the separated plasma can beanalyzed electrically using one or more electrodes instead of, or inaddition to, being analyzed optically. This analysis may occur withinthe same device, or within a different device. For example, in certainembodiments, an optical analysis device can separate blood intocomponents, analyze the components, and then allow the components to betransported to another analysis device that can further analyze thecomponents (e.g., using electrical and/or electrochemical measurements).

An anticoagulant, such as, for example, heparin can be added to thesample before centrifugation to prevent clotting. The fluid-handlingsystem 404 can be used with a variety of anticoagulants, includinganticoagulants supplied by a hospital or other user of the monitoringsystem 400. A detergent solution formed by mixing detergent powder froma pouch connected to the fluid-handling system 404 with saline can beused to periodically clean residual protein and other sample remnantsfrom one or more components of the fluid-handling system 404, such asthe sample holder. Sample fluid to which anticoagulant has been addedand used detergent solution can be transferred into the waste bladder.

The system 400 shown in FIG. 4 includes an optical system 412 that canmeasure optical properties (e.g., transmission) of a fluid sample (or aportion thereof). In some embodiments, the optical system 412 measurestransmission in the mid-infrared range of the spectrum. In someembodiments, the optical system 412 includes a spectrometer thatmeasures the transmission of broadband infrared light through a portionof a sample holder filled with fluid. The spectrometer need not comeinto direct contact with the sample. As used herein, the term “sampleholder” is a broad term that carries its ordinary meaning as an objectthat can provide a place for fluid. The fluid can enter the sampleholder by flowing.

In some embodiments, the optical system 412 includes a filter wheel thatcontains one or more filters. In some embodiments, more than ten filterscan be included, for example twelve or fifteen filters. In someembodiments, more than 20 filters (e.g., twenty-five filters) aremounted on the filter wheel. The optical system 412 includes a lightsource that passes light through a filter and the sample holder to adetector. In some embodiments, a stepper motor moves the filter wheel inorder to position a selected filter in the path of the light. An opticalencoder can also be used to finely position one or more filters. In someembodiments, one or more tunable filters may be used to filter lightinto multiple wavelengths. The one or more tunable filters may providethe multiple wavelengths of light at the same time or at different times(e.g., sequentially). The light source included in the optical system412 may emit radiation in the ultraviolet, visible, near-infrared,mid-infrared, and/or far-infrared regions of the electromagneticspectrum. In some embodiments, the light source can be a broadbandsource that emits radiation in a broad spectral region (e.g., from about1500 nm to about 6000 nm). In other embodiments, the light source mayemit radiation at certain specific wavelengths. The light source maycomprise one or more light emitting diodes (LEDs) emitting radiation atone or more wavelengths in the radiation regions described herein. Inother embodiments, the light source may comprise one or more lasermodules emitting radiation at one or more wavelengths. The laser modulesmay comprise a solid state laser (e.g., a Nd:YAG laser), a semiconductorbased laser (e.g., a GaAs and/or InGaAsP laser), and/or a gas laser(e.g., an Ar-ion laser). In some embodiments, the laser modules maycomprise a fiber laser. The laser modules may emit radiation at certainfixed wavelengths. In some embodiments, the emission wavelength of thelaser module(s) may be tunable over a wide spectral range (e.g., about30 nm to about 100 nm). In some embodiments, the light source includedin the optical system 412 may be a thermal infrared emitter. The lightsource can comprise a resistive heating element, which, in someembodiments, may be integrated on a thin dielectric membrane on amicromachined silicon structure. In one embodiment the light source isgenerally similar to the electrical modulated thermal infrared radiationsource, IRSource™, available from the Axetris Microsystems division ofLeister Technologies, LLC (Itasca, Ill.).

The optical system 412 can be controlled by an optical system controller413. The optical system controller can, in some embodiments, beintegrated into the optical system 412. In some embodiments, the fluidsystem controller 405 and the optical system controller 413 cancommunicate with each other as indicated by the line 411. In someembodiments, the function of these two controllers can be integrated anda single controller can control both the fluid-handling system 404 andthe optical system 412. Such an integrated control can be advantageousbecause the two systems are preferably integrated, and the opticalsystem 412 is preferably configured to analyze the very same fluidhandled by the fluid-handling system 404. Indeed, portions of thefluid-handling system 404 (e.g., the sample holder described above withrespect to the second disposable subsystem 410 and/or at least somecomponents of a centrifuge) can also be components of the optical system412. Accordingly, the fluid-handling system 404 can be controlled toobtain a fluid sample for analysis by optical system 412, when the fluidsample arrives, the optical system 412 can be controlled to analyze thesample, and when the analysis is complete (or before), thefluid-handling system 404 can be controlled to return some of the sampleto the fluid source 402 and/or discard some of the sample, asappropriate.

The system 400 shown in FIG. 4 includes a display system 414 thatprovides for communication of information to a user of the system 400.In some embodiments, the display 414 can be replaced by or supplementedwith other communication devices that communicate in non-visual ways.The display system 414 can include a display processor that controls orproduces an interface to communicate information to the user. Thedisplay system 414 can include a display screen. One or more parameterssuch as, for example, blood glucose concentration, system 400 operatingparameters, and/or other operating parameters can be displayed on amonitor (not shown) associated with the system 400. An example of oneway such information can be displayed is shown in FIGS. 24 and 25. Insome embodiments, the display system 414 can communicate measuredphysiological parameters and/or operating parameters to a computersystem over a communications connection.

The system 400 shown in FIG. 4 includes an algorithm processor 416 thatcan receive spectral information, such as optical density (OD) values(or other analog or digital optical data) from the optical system 412and or the optical system controller 413. In some embodiments, thealgorithm processor 416 calculates one or more physiological parametersand can analyze the spectral information. Thus, for example and withoutlimitation, a model can be used that determines, based on the spectralinformation, physiological parameters of fluid from the fluid source402. The algorithm processor 416, a controller that may be part of thedisplay system 414, and any embedded controllers within the system 400can be connected to one another with a communications bus.

Some embodiments of the systems described herein (e.g., the system 400),as well as some embodiments of each method described herein, can includea computer program accessible to and/or executable by a processingsystem, e.g., a one or more processors and memories that are part of anembedded system. Indeed, the controllers may comprise one or morecomputers and/or may use software. Thus, as will be appreciated by thoseskilled in the art, various embodiments may be embodied as a method, anapparatus such as a special purpose apparatus, an apparatus such as adata processing system, or a carrier medium, e.g., a computer programproduct. The carrier medium carries one or more computer readable codesegments for controlling a processing system to implement a method.Accordingly, various embodiments may take the form of a method, anentirely hardware embodiment, an entirely software embodiment or anembodiment combining software and hardware aspects. Furthermore, any oneor more of the disclosed methods (including but not limited to thedisclosed methods of measurement analysis, interferent determination,and/or calibration constant generation) may be stored as one or morecomputer readable code segments or data compilations on a carriermedium. Any suitable computer readable carrier medium may be usedincluding a magnetic storage device such as a diskette or a hard disk; amemory cartridge, module, card or chip (either alone or installed withina larger device); or an optical storage device such as a CD or DVD.

Fluid Handling System

The generalized fluid-handling system 404 can have variousconfigurations. In this context, FIG. 5 schematically illustrates thelayout of an example embodiment of a fluid system 510. In this schematicrepresentation, various components are depicted that may be part of anon-disposable subsystem 406, a first disposable subsystem 408, a seconddisposable subsystem 410, and/or an optical system 412. The fluid system510 is described practically to show an example cycle as fluid is drawnand analyzed.

In addition to the reference numerals used below, the various portionsof the illustrated fluid system 510 are labeled for convenience withletters to suggest their roles as follows: T# indicates a section oftubing. C# indicates a connector that joins multiple tubing sections. V#indicates a valve. BS# indicates a bubble sensor or ultrasonic airdetector. N# indicates a needle (e.g., a needle that injects sample intoa sample holder). PS# indicates a pressure sensor (e.g., a reusablepressure sensor). Pump# indicates a fluid pump (e.g., a syringe pumpwith a disposable body and reusable drive). “Hb 12” indicates a sensorfor hemoglobin (e.g., a dilution sensor that can detect hemoglobinoptically).

The term “valve” as used herein is a broad term and is used, inaccordance with its ordinary meaning, to refer to any flow regulatingdevice. For example, the term “valve” can include, without limitation,any device or system that can controllably allow, prevent, or inhibitthe flow of fluid through a fluid passageway. The term “valve” caninclude some or all of the following, alone or in combination: pinchvalves, rotary valves, stop cocks, pressure valves, shuttle valves,mechanical valves, electrical valves, electro-mechanical flowregulators, etc. In some embodiments, a valve can regulate flow usinggravitational methods or by applying electrical voltages or by both.

The term “pump” as used herein is a broad term and is used, inaccordance with its ordinary meaning, to refer to any device that canurge fluid flow. For example, the term “pump” can include anycombination of the following: syringe pumps, peristaltic pumps, vacuumpumps, electrical pumps, mechanical pumps, hydraulic pumps, etc. Pumpsand/or pump components that are suitable for use with some embodimentscan be obtained, for example, from or through Hospira.

The function of the valves, pumps, actuators, drivers, motors (e.g., thecentrifuge motor), etc. described below is controlled by one or morecontrollers (e.g., the fluid system controller 405, the optical systemcontroller 413, etc.) The controllers can include software, computermemory, electrical and mechanical connections to the controlledcomponents, etc.

At the start of a measurement cycle, most lines, including a patienttube 512 (T1), an Arrival sensor tube 528 (T4), an anticoagulant valvetube 534 (T3), and a sample cell 548 can be filled with saline that canbe introduced into the system through the infusion tube 514 and thesaline tube 516, and which can come from an infusion pump 518 and/or asaline bag 520. The infusion pump 518 and the saline bag 520 can beprovided separately from the system 510. For example, a hospital can useexisting saline bags and infusion pumps to interface with the describedsystem. The infusion valve 521 can be open to allow saline to flow intothe tube 512 (T1).

Before drawing a sample, the saline in part of the system 510 can bereplaced with air. Thus, for example, the following valves can beclosed: air valve 503 (PV0), the detergent tank valve 559 (V7 b), 566(V3 b), 523 (V0), 529 (V7 a), and 563 (V2 b). At the same time, thefollowing valves can be open: valves 531 (V1 a), 533 (V3 a) and 577 (V4a). Simultaneously, a second pump 532 (pump #0) pumps air through thesystem 510 (including tube 534 (T3), sample cell 548, and tube 556(T6)), pushing saline through tube 534 (T3) and sample cell 548 into awaste bladder 554.

Next, a sample can be drawn. With the valves 542 (PV1), 559 (V7 b), and561 (V4 b) closed, a first pump 522 (pump #1) is actuated to draw samplefluid to be analyzed (e.g. blood) from a fluid source (e.g., alaboratory sample container, a living patient, etc.) up into the patienttube 512 (T1), through the tube past the two flanking portions of theopen pinch-valve 523 (V0), through the first connector 524 (C1), intothe looped tube 530, past the arrival sensor 526 (Hb12), and into thearrival sensor tube 528 (T4). The arrival sensor 526 may be used todetect the presence of blood in the tube 528 (T4). For example in someembodiments, the arrival sensor 526 may comprise a hemoglobin sensor. Insome other embodiments, the arrival sensor 526 may comprise a colorsensor that detects the color of fluid flowing through the tube 528(T4). During this process, the valve 529 (V7 a) and 523 (V0) are open tofluid flow, and the valves 531 (V1 a), 533 (V3 a), 542 (PV1), 559 (V7b), and 561 (V4 b) can be closed and therefore block (or substantiallyblock) fluid flow by pinching the tube.

Before drawing the sample, the tubes 512 (T1) and 528 (T4) are filledwith saline and the hemoglobin (Hb) level is zero. The tubes that arefilled with saline are in fluid communication with the sample source(e.g., the fluid source 402). The sample source can be the vessels of aliving human or a pool of liquid in a laboratory sample container, forexample. When the saline is drawn toward the first pump 522, fluid to beanalyzed is also drawn into the system because of the suction forces inthe closed fluid system. Thus, the first pump 522 draws a relativelycontinuous column of fluid that first comprises generally nondilutedsaline, then a mixture of saline and sample fluid (e.g., blood), andthen eventually nondiluted sample fluid. In the example illustratedhere, the sample fluid is blood.

The arrival sensor 526 (Hb12) can detect and/or verify the presence ofblood in the tubes. For example, in some embodiments, the arrival sensor526 can determine the color of the fluid in the tubes. In someembodiments, the arrival sensor 526 (Hb12) can detect the level ofHemoglobin in the sample fluid. As blood starts to arrive at the arrivalsensor 526 (Hb12), the sensed hemoglobin level rises. A hemoglobin levelcan be selected, and the system can be pre-set to determine when thatlevel is reached. A controller such as the fluid system controller 405of FIG. 4 can be used to set and react to the pre-set value, forexample. In some embodiments, when the sensed hemoglobin level reachesthe pre-set value, substantially undiluted sample is present at thefirst connector 524 (C1). The preset value can depend, in part, on thelength and diameter of any tubes and/or passages traversed by thesample. In some embodiments, the pre-set value can be reached afterapproximately 2 mL of fluid (e.g., blood) has been drawn from a fluidsource. A nondiluted sample can be, for example, a blood sample that isnot diluted with saline solution, but instead has the characteristics ofthe rest of the blood flowing through a patient's body. A loop of tubing530 (e.g., a 1-mL loop) can be advantageously positioned as illustratedto help insure that undiluted fluid (e.g., undiluted blood) is presentat the first connector 524 (C1) when the arrival sensor 526 registersthat the preset Hb threshold is crossed. The loop of tubing 530 providesadditional length to the Arrival sensor tube 528 (T4) to make it lesslikely that the portion of the fluid column in the tubing at the firstconnector 524 (C1) has advanced all the way past the mixture of salineand sample fluid, and the nondiluted blood portion of that fluid hasreached the first connector 524 (C1).

In some embodiments, when nondiluted blood is present at the firstconnector 524 (C1), a sample is mixed with an anticoagulant and isdirected toward the sample cell 548. An amount of anticoagulant (e.g.,heparin) can be introduced into the tube 534 (T3), and then theundiluted blood is mixed with the anticoagulant. A heparin vial 538(e.g., an insertable vial provided independently by the user of thesystem 510) can be connected to a tube 540. An anticoagulant valve 541(which can be a shuttle valve, for example) can be configured to connectto both the tube 540 and the anticoagulant valve tube 534 (T3). Thevalve can open the tube 540 to a suction force (e.g., created by thepump 532), allowing heparin to be drawn from the vial 538 into the valve541. Then, the anticoagulant valve 541 can slide the heparin over intofluid communication with the anticoagulant valve tube 534 (T3). Theanticoagulant valve 541 can then return to its previous position. Thus,heparin can be shuttled from the tube 540 into the anticoagulant valvetube 534 (T3) to provide a controlled amount of heparin into the tube534 (T3).

With the valves 542 (PV1), 559 (V7 b), 561 (V4 b), 523 (V0), 531 (V1 a),566 (V3 b), and 563 (V2 b) closed, and the valves 529 (V7 a) and 533 (V3a) open, first pump 522 (pump #1) pushes the sample from tube 528 (T4)into tube 534 (T3), where the sample mixes with the heparin injected bythe anticoagulant valve 541 as it flows through the system 510. As thesample proceeds through the tube 534 (T3), the air that was previouslyintroduced into the tube 534 (T3) is displaced. The sample continues toflow until a bubble sensor 535 (BS9) indicates a change from air to aliquid, and thus the arrival of a sample at the bubble sensor. In someembodiments, the volume of tube 534 (T3) from connector 524 (C1) tobubble sensor 535 (BS9) is a known and/or engineered amount, and may beapproximately 500 μL, 200 μL or 100 μL, for example. In someembodiments, the volume of tube 534 (T3) from connector 524 (C1) tobubble sensor 535 (BS9) may be approximately less than 10 ml.

When bubble sensor 535 (BS9) indicates the presence of a sample, theremainder of the sampled blood can be returned to its source (e.g., thepatient veins or arteries). The first pump 522 (pump #1) pushes theblood out of the Arrival sensor tube 528 (T4) and back to the patient byopening the valve 523 (V0), closing the valves 531 (V1 a) and 533 (V3a), and keeping the valve 529 (V7 a) open. The Arrival sensor tube 528(T4) is preferably flushed with approximately 2 mL of saline. This canbe accomplished by closing the valve 529 (V7 a), opening the valve 542(PV1), drawing saline from the saline source 520 into the tube 544,closing the valve 542 (PV1), opening the valve 529 (V7 a), and forcingthe saline down the Arrival sensor tube 528 (T4) with the pump 522. Insome embodiments, less than two minutes elapse between the time thatblood is drawn from the patient and the time that the blood is returnedto the patient.

Following return of the unused patient blood sample, the sample ispushed up the anticoagulant valve tube 534 (T3), through the secondconnector 546 (C2), and into the sample cell 548, which can be locatedon the centrifuge rotor 550. This fluid movement is facilitated by thecoordinated action (either pushing or drawing fluid) of the pump 522(pump #1), the pump 532 (pump #0), and the various illustrated valves.In particular, valve 531 (V1 a) can be opened, and valves 503 (PV0) and559 (V7 b) can be closed. Pump movement and valve position correspondingto each stage of fluid movement can be coordinated by one ore multiplecontrollers, such as the fluid system controller 405 of FIG. 4.

After the unused sample is returned to the patient, the sample can bedivided into separate slugs before being delivered into the sample cell548. Thus, for example, valve 533 (V3 a) is opened, valves 566 (V3 b),523 (V0) and 529 (V7 a) are closed, and the pump 532 (pump #0) uses airto push the sample toward sample cell 548. In some embodiments, thesample (for example, 200 μL or 100 μL) is divided into multiple (e.g.,more than two, five, or four) “slugs” of sample, each separated by asmall amount of air. As used herein, the term “slug” refers to acontinuous column of fluid that can be relatively short. Slugs can beseparated from one another by small amounts of air (or bubbles) that canbe present at intervals in the tube. In some embodiments, the slugs areformed by injecting or drawing air into fluid in the first connector 546(C2).

In some embodiments, when the leading edge of the sample reaches bloodsensor 552 (BS14), a small amount of air (the first “bubble”) isinjected at a connector C6. This bubble helps define the first “slug” ofliquid, which extends from the bubble sensor to the first bubble. Insome embodiments, the valves 533 (V3 a) and 566 (V3 b) are alternatelyopened and closed to form a bubble at connector C6, and the sample ispushed toward the sample cell 548. Thus, for example, with pump 532actuated, valve 566 V(3 b) is briefly opened and valve 533 (V3 a) isbriefly closed to inject a first air bubble into the sample.

In some embodiments, the volume of the tube 534 (T3) from the connector546 (C2) to the bubble sensor 552 (BS14) is less than the volume of tube534 (T3) from the connector 524 (C1) to the bubble sensor 535 (BS9).Thus, for example and without limitation, the volume of the tube 534(T3) from the connector 524 (C1) to the bubble sensor 535 (BS9) can bein the range of approximately 80 μL to approximately 120 μL, (e.g., 100μL,) and the volume of the tube 534 (T3) from the connector 546 (C2) tothe bubble sensor 552 (BS14) can be in the range of approximately 5 μLto approximately 25 μL (e.g., 15 μL). In some embodiments, multipleblood slugs are created. For example, more than two blood slugs can becreated, each having a different volume. In some embodiments, five bloodslugs are created, each having approximately the same volume ofapproximately 20 μL each. In some embodiments, three blood slugs arecreated, the first two having a volume of 10 μL and the last having avolume of 20 μL. In some embodiments, four blood slugs are created; thefirst three blood slugs can have a volume of approximately 15 μL and thefourth can have a volume of approximately 35 μL.

A second slug can be prepared by opening the valve 533 (V3 a), closingthe valve 566 (V3 b), with pump 532 (pump #0) operating to push thefirst slug through a first sample cell holder interface tube 582 (N1),through the sample cell 548, through a second sample cell holderinterface tube 584 (N2), and toward the waste bladder 554. When thefirst bubble reaches the bubble sensor 552 (BS 14), the open/closedconfigurations of valves 533 (V3 a) and 566 (V3 b) are reversed, and asecond bubble is injected into the sample, as before. A third slug canbe prepared in the same manner as the second (pushing the second bubbleto bubble sensor 552 (BS 14) and injecting a third bubble). After theinjection of the third air bubble, the sample can be pushed throughsystem 510 until the end of the sample is detected by bubble sensor 552(BS 14). The system can be designed such that when the end of the samplereaches this point, the last portion of the sample (a fourth slug) iswithin the sample cell 548, and the pump 532 can stop forcing the fluidcolumn through the anticoagulant valve tube 534 (T3) so that the fourthslug remains within the sample cell 548. Thus, the first three bloodslugs can serve to flush any residual saline out the sample cell 548.The three leading slugs can be deposited in the waste bladder 554 bypassing through the tube 556 (T6) and past the tube-flanking portions ofthe open pinch valve 557 (V4 a).

In some embodiments, the fourth blood slug is centrifuged for a givenlength of time (e.g., more than 1 minute, five minutes, or 2 minutes, totake three advantageous examples) at a relatively fast speed (e.g., 7200RPM, 5000 RPM, or 4500 RPM, to take three examples). Thus, for example,the sample cell holder interface tubes 582 (N1) and 584 (N2) disconnectthe sample cell 548 from the tubes 534 (T3) and 562 (T7), permitting thecentrifuge rotor 550 and the sample cell 548 to spin together. Spinningseparates a sample (e.g., blood) into its components, isolates theplasma, and positions the plasma in the sample cell 548 for measurement.The centrifuge 550 can be stopped with the sample cell 548 in a beam ofradiation (not shown) for analysis. The radiation, a detector, and logiccan be used to analyze a portion of the sample (e.g., the plasma)spectroscopically (e.g., for glucose, lactate, or other analyteconcentration). In some embodiments, some or all of the separatedcomponents (e.g., the isolated plasma) may be transported to a differentanalysis chamber. For example, another analysis chamber can have one ormore electrodes in electrical communication with the chamber's contents,and the separated components may be analyzed electrically. At anysuitable point, one or more of the separated components can betransported to the waste bladder 554 when no longer needed. In somechemical analysis systems and apparatus, the separated components areanalyzed electrically. Analysis devices may be connected serially, forexample, so that the analyzed substance from an optical analysis system(e.g., an OPTISCANNER™ fluid analyzer) can be transferred to anindependent analysis device (e.g., a chemical analysis device) forsubsequent analysis. In certain embodiments, the analysis devices areintegrated into a single system. Many variations are possible.

In some embodiments, portions of the system 510 that contain blood afterthe sample cell 548 has been provided with a sample are cleaned toprevent blood from clotting. Accordingly, the centrifuge rotor 550 caninclude two passageways for fluid that may be connected to the samplecell holder interface tubes 582 (N1) and 584 (N2). One passageway issample cell 548, and a second passageway is a shunt 586. An embodimentof the shunt 586 is illustrated in more detail in FIG. 16 (see referencenumeral 1586).

The shunt 586 can allow cleaner (e.g., a detergent such as tergazyme A)to flow through and clean the sample cell holder interface tubes withoutflowing through the sample cell 548. After the sample cell 548 isprovided with a sample, the interface tubes 582 (N1) and 584 (N2) aredisconnected from the sample cell 548, the centrifuge rotor 550 isrotated to align the shunt 586 with the interface tubes 582 (N1) and 584(N2), and the interface tubes are connected with the shunt. With theshunt in place, the detergent tank 559 is pressurized by the second pump532 (pump #0) with valves 561 (V4 b) and 563 (V2 b) open and valves 557(V4 a) and 533 (V3 a) closed to flush the cleaning solution back throughthe interface tubes 582 (N1) and 584 (N2) and into the waste bladder554. Subsequently, saline can be drawn from the saline bag 520 for asaline flush. This flush pushes saline through the Arrival sensor tube528 (T4), the anticoagulant valve tube 534 (T3), the sample cell 548,and the waste tube 556 (T6). Thus, in some embodiments, the followingvalves are open for this flush: 529 (V7 a), 533 (V3 a), 557 (V4 a), andthe following valves are closed: 542 (PV1), 523 (V0), 531 (V1 a), 566(V3 b), 563 (V2 b), and 561 (V4 b).

Following analysis, the second pump 532 (pump #0) flushes the samplecell 548 and sends the flushed contents to the waste bladder 554. Thisflush can be done with a cleaning solution from the detergent tank 558.In some embodiments, the detergent tank valve 559 (V7 b) is open,providing fluid communication between the second pump 532 and thedetergent tank 558. The second pump 532 forces cleaning solution fromthe detergent tank 558 between the tube-flanking portions of the openpinch valve 561 and through the tube 562 (T7). The cleaning flush canpass through the sample cell 548, through the second connector 546,through the tube 564 (T5) and the open valve 563 (V2 b), and into thewaste bladder 554.

Subsequently, the first pump 522 (pump #1) can flush the cleaningsolution out of the sample cell 548 using saline in drawn from thesaline bag 520. This flush pushes saline through the Arrival sensor tube528 (T4), the anticoagulant valve tube 534 (T3), the sample cell 548,and the waste tube 556 (T6). Thus, in some embodiments, the followingvalves are open for this flush: 529 (V7 a), 533 (V3 a), 557 (V4 a), andthe following valves are closed: 542 (PV1), 523 (V0), 531 (Via), 566 (V3b), 563 (V2 b), and 561 (V4 b).

When the fluid source is a living entity such as a patient, a low flowof saline (e.g., 1-5 mL/hr) is preferably moved through the patient tube512 (T1) and into the patient to keep the patient's vessel open (e.g.,to establish a keep vessel open, or “KVO” flow). This KVO flow can betemporarily interrupted when fluid is drawn into the fluid system 510.The source of this KVO flow can be the infusion pump 518, the third pump568 (pump #3), or the first pump 522 (pump #1). In some embodiments, theinfusion pump 518 can run continuously throughout the measurement cycledescribed above. This continuous flow can advantageously avoid anyalarms that may be triggered if the infusion pump 518 senses that theflow has stopped or changed in some other way. In some embodiments, whenthe infusion valve 521 closes to allow pump 522 (pump #1) to withdrawfluid from a fluid source (e.g., a patient), the third pump 568 (pump#3) can withdraw fluid through the connector 570, thus allowing theinfusion pump 518 to continue pumping normally as if the fluid path wasnot blocked by the infusion valve 521. If the measurement cycle is abouttwo minutes long, this withdrawal by the third pump 568 can continue forapproximately two minutes. Once the infusion valve 521 is open again,the third pump 568 (pump #3) can reverse and insert the saline back intothe system at a low flow rate. Preferably, the time between measurementcycles is longer than the measurement cycle itself (for example, thetime interval can be longer than ten minutes, shorter than ten minutes,shorter than five minutes, longer than two minutes, longer than oneminute, etc.). Accordingly, the third pump 568 can insert fluid backinto the system at a lower rate than it withdrew that fluid. This canhelp prevent an alarm by the infusion pump.

FIG. 6 schematically illustrates another embodiment of a fluid systemthat can be part of a system for withdrawing and analyzing fluidsamples. In this embodiment, the anticoagulant valve 541 has beenreplaced with a syringe-style pump 588 (Pump Heparin) and a series ofpinch valves around a junction between tubes. For example, a heparinpinch valve 589 (Vhep) can be closed to prevent flow from or to the pump588, and a heparin waste pinch valve 590 can be closed to prevent flowfrom or to the waste container from this junction through the heparinwaste tube 591. This embodiment also illustrates the shunt 592schematically. Other differences from FIG. 5 include the check valve 593located near the detergent tank 558 and the patient loop 594. Thereference letters D, for example, the one indicated at 595, refer tocomponents that are advantageously located on the door. The referenceletters M, for example, the one indicated at 596, refer to componentsthat are advantageously located on the monitor. The reference letters B,for example, the one indicated at 597, refer to components that can beadvantageously located on both the door and the monitor.

In some embodiments, the system 400 (see FIG. 4), the apparatus 100 (seeFIG. 1), or even the monitoring device 102 (see FIG. 1) itself can alsoactively function not only to monitor analyte levels (e.g., glucose),but also to change and/or control analyte levels. Thus, the monitoringdevice 102 can be both a monitoring and an infusing device. In someembodiments, the fluid handling system 510 can include an optionalanalyte control subsystem 2780 that will be further described below (seediscussion of analyte control).

In certain embodiments, analyte levels in a patient can be adjusteddirectly (e.g., by infusing or extracting glucose) or indirectly (e.g.,by infusing or extracting insulin). FIG. 6 illustrates one way ofproviding this function. The infusion pinch valve 598 (V8) can allow theport sharing pump 599 (compare to the third pump 568 (pump #3) in FIG.5) to serve two roles. In the first role, it can serve as a “portsharing” pump. The port sharing function is described with respect tothe third pump 568 (pump #3) of FIG. 5, where the third pump 568 (pump#3) can withdraw fluid through the connector 570, thus allowing theinfusion pump 518 to continue pumping normally as if the fluid path wasnot blocked by the infusion valve 521. In the second role, the portsharing pump 599 can serve as an infusion pump. The infusion pump roleallows the port sharing pump 599 to draw a substance (e.g., glucose,saline, etc.) from another source when the infusion pinch valve 598 isopen, and then to infuse that substance into the system or the patientwhen the infusion pinch valve 598 is closed. This can occur, forexample, in order to change the level of a substance in a patient inresponse to a reading by the monitor that the substance is too low. Insome embodiments, one or more of the pumps may comprise a reversibleinfusion pump configured to interrupt the flow of the infusion fluid anddraw a sample of blood for analysis.

Mechanical/Fluid System Interface

FIG. 7 is an oblique schematic depiction of a modular monitoring device700, which can correspond to the monitoring device 102. The modularmonitoring device 700 includes a body portion 702 having a receptacle704, which can be accessed by moving a movable portion 706. Thereceptacle 704 can include connectors (e.g., rails, slots, protrusions,resting surfaces, etc.) with which a removable portion 710 caninterface. In some embodiments, portions of a fluidic system thatdirectly contact fluid are incorporated into one or more removableportions (e.g., one or more disposable cassettes, sample holders, tubingcards, etc.). For example, a removable portion 710 can house at least aportion of the fluid system 510 described previously, including portionsthat contact sample fluids, saline, detergent solution, and/oranticoagulant.

In some embodiments, a non-disposable fluid-handling subsystem 708 isdisposed within the body portion 702 of the monitoring device 700. Thefirst removable portion 710 can include one or more openings that allowportions of the non-disposable fluid-handling subsystem 708 to interfacewith the removable portion 710. For example, the non-disposablefluid-handling subsystem 708 can include one or more pinch valves thatare designed to extend through such openings to engage one or moresections of tubing. When the first removable portion 710 is present in acorresponding first receptacle 704, actuation of the pinch valves canselectively close sections of tubing within the removable portion. Thenon-disposable fluid-handling subsystem 708 can also include one or moresensors that interface with connectors, tubing sections, or pumpslocated within the first removable portion 710. The non-disposablefluid-handling subsystem 708 can also include one or more actuators(e.g., motors) that can actuate moveable portions (e.g., the plunger ofa syringe) that may be located in the removable portion F10. A portionof the non-disposable fluid-handling subsystem 708 can be located on orin the moveable portion F06 (which can be a door having a slide or ahinge, a detachable face portion, etc.).

In the embodiment shown in FIG. 7, the monitoring device 700 includes anoptical system 714 disposed within the body portion 702. The opticalsystem 714 can include a light source and a detector that are adapted toperform measurements on fluids within a sample holder (not shown). Thelight source may comprise a fixed wavelength light source and/or atunable light source. The light source may comprise one or more sourcesincluding, for example, broadband sources, LEDs, and lasers. In someembodiments, the sample holder comprises a removable portion, which canbe associated with or disassociated from the removable portion F10. Thesample holder can include an optical window through which the opticalsystem 714 can emit radiation for measuring properties of a fluid in thesample holder. The optical system 714 can include other components suchas, for example, a power supply, a centrifuge motor, a filter wheel,and/or a beam splitter.

In some embodiments, the removable portion 710 and the sample holder areadapted to be in fluid communication with each other. For example, theremovable portion 710 can include a retractable injector that injectsfluids into a sample holder. In some embodiments, the sample holder cancomprise or be disposed in a second removable portion (not shown). Insome embodiments, the injector can be retracted to allow the centrifugeto rotate the sample holder freely.

The body portion 702 of the monitoring device 700 can also include oneor more connectors for an external battery (not shown). The externalbattery can serve as a backup emergency power source in the event that aprimary emergency power source such as, for example, an internal battery(not shown) is exhausted.

FIG. 7 shows an embodiment of a system having subcomponents illustratedschematically. By way of a more detailed (but nevertheless non-limiting)example, FIG. 8 and FIG. 9 show more details of the shape and physicalconfiguration of a sample embodiment.

FIG. 8 shows a cut-away side view of a monitoring device 800 (which cancorrespond, for example, to the device 102 shown in FIG. 1). The device800 includes a casing 802. The monitoring device 800 can have a fluidsystem. For example, the fluid system can have subsystems, and a portionor portions thereof can be disposable, as schematically depicted in FIG.4. As depicted in FIG. 8, the fluid system is generally located at theleft-hand portion of the casing 802, as indicated by the reference 801.The monitoring device 800 can also have an optical system. In theillustrated embodiment, the optical system is generally located in theupper portion of the casing 802, as indicated by the reference 803.Advantageously, however, the fluid system 801 and the optical system 803can both be integrated together such that fluid flows generally througha portion of the optical system 803, and such that radiation flowsgenerally through a portion of the fluid system 801.

Depicted in FIG. 8 are examples of ways in which components of thedevice 800 mounted within the casing 802 can interface with componentsof the device 800 that comprise disposable portions. Not all componentsof the device 800 are shown in FIG. 8. A disposable portion 804 having avariety of components is shown in the casing 802. In some embodiments,one or more actuators 808 housed within the casing 802, operate syringebodies 810 located within a disposable portion 804. The syringe bodies810 are connected to sections of tubing 816 that move fluid amongvarious components of the system. The movement of fluid is at leastpartially controlled by the action of one or more pinch valves 812positioned within the casing 802. The pinch valves 812 have arms 814that extend within the disposable portion 804. Movement of the arms 814can constrict a section of tubing 816.

In some embodiments, a sample cell holder 820 can engage a centrifugemotor 818 mounted within the casing 802 of the device 800. A filterwheel motor 822 disposed within the housing 802 rotates a filter wheel824, and in some embodiments, aligns one or more filters with an opticalpath. An optical path can originate at a source 826 within the housing802 that can be configured to emit a beam of radiation (e.g., infraredradiation, visible radiation, ultraviolet radiation, etc.) through thefilter and the sample cell holder 820 and to a detector 828. A detector828 can measure the optical density of the light when it reaches thedetector.

FIG. 9 shows a cut-away perspective view of an alternative embodiment ofa monitoring device 900. Many features similar to those illustrated inFIG. 8 are depicted in this illustration of an alternative embodiment. Afluid system 901 can be partially seen. The disposable portion 904 isshown in an operative position within the device. One of the actuators808 can be seen next to a syringe body 910 that is located within thedisposable portion 904. Some pinch valves 912 are shown next to afluid-handling portion of the disposable portion 904. In this figure, anoptical system 903 can also be partially seen. The sample holder 920 islocated underneath the centrifuge motor 918. The filter wheel motor 922is positioned near the radiation source 926, and the detector 928 isalso illustrated.

FIG. 10 illustrates two views of a cartridge 1000 that can interfacewith a fluid system such as the fluid system 510 of FIG. 5. Thecartridge 1000 can be configured for insertion into a receptacle of thedevice 800 of FIG. 8 and/or the device 900 shown in FIG. 9. In someembodiments, the cartridge 1000 can comprise a portion that isdisposable and a portion that is reusable. In some embodiments, thecartridge 1000 can be disposable. The cartridge 1000 can fill the roleof the removable portion 710 of FIG. 7, for example. In someembodiments, the cartridge 1000 can be used for a system having only onedisposable subsystem, making it a simple matter for a health careprovider to replace and/or track usage time of the disposable portion.In some embodiments, the cartridge 1000 includes one or more featuresthat facilitate insertion of the cartridge 1000 into a correspondingreceptacle. For example, the cartridge 1000 can be shaped so as topromote insertion of the cartridge 1000 in the correct orientation. Thecartridge 1000 can also include labeling or coloring affixed to orintegrated with the cartridge's exterior casing that help a handlerinsert the cartridge 1000 into a receptacle properly.

The cartridge 1000 can include one or more ports for connecting tomaterial sources or receptacles. Such ports can be provided to connectto, for example, a saline source, an infusion pump, a sample source,and/or a source of gas (e.g., air, nitrogen, etc.). The ports can beconnected to sections of tubing within the cartridge 1000. In someembodiments, the sections of tubing are opaque or covered so that fluidswithin the tubing cannot be seen, and in some embodiments, sections oftubing are transparent to allow interior contents (e.g., fluid) to beseen from outside.

The cartridge 1000 shown in FIG. 10 can include a sample injector 1006.The sample injector 1006 can be configured to inject at least a portionof a sample into a sample holder (see, e.g., the sample cell 548), whichcan also be incorporated into the cartridge 1000. The sample injector1006 can include, for example, the sample cell holder interface tubes582 (N1) and 584 (N2) of FIG. 5, embodiments of which are alsoillustrated in FIG. 15.

The housing of the cartridge 1000 can include a tubing portion 1008containing within it a card having one or more sections of tubing. Insome embodiments, the body of the cartridge 1000 includes one or moreapertures 1009 through which various components, such as, for example,pinch valves and sensors, can interface with the fluid-handling portioncontained in the cartridge 1000. The sections of tubing found in thetubing portion 1008 can be aligned with the apertures 1009 in order toimplement at least some of the functionality shown in the fluid system510 of FIG. 5.

The cartridge 1000 can include a pouch space (not shown) that cancomprise one or more components of the fluid system 510. For example,one or more pouches and/or bladders can be disposed in the pouch space(not shown). In some embodiments, a cleaner pouch and/or a waste bladdercan be housed in a pouch space. The waste bladder can be placed underthe cleaner pouch such that, as detergent is removed from the cleanerpouch, the waste bladder has more room to fill. The components placed inthe pouch space (not shown) can also be placed side-by-side or in anyother suitable configuration.

The cartridge 1000 can include one or more pumps 1016 that facilitatemovement of fluid within the fluid system 510. Each of the pump housings1016 can contain, for example, a syringe pump having a plunger. Theplunger can be configured to interface with an actuator outside thecartridge 1000. For example, a portion of the pump that interfaces withan actuator can be exposed to the exterior of the cartridge 1000 housingby one or more apertures 1018 in the housing.

The cartridge 1000 can have an optical interface portion 1030 that isconfigured to interface with (or comprise a portion of) an opticalsystem. In the illustrated embodiment, the optical interface portion1030 can pivot around a pivot structure 1032. The optical interfaceportion 1030 can house a sample holder (not shown) in a chamber that canallow the sample holder to rotate. The sample holder can be held by acentrifuge interface 1036 that can be configured to engage a centrifugemotor (not shown). When the cartridge 1000 is being inserted into asystem, the orientation of the optical interface portion 1030 can bedifferent than when it is functioning within the system.

In some embodiments, the cartridge 1000 is designed for single patientuse. The cartridge 1000 may also be disposable and/or designed forreplacement after a period of operation. For example, in someembodiments, if the cartridge 1000 is installed in a continuouslyoperating monitoring device that performs four measurements per hour,the waste bladder may become filled or the detergent in the cleanerpouch depleted after about three days. The cartridge 1000 can bereplaced before the detergent and waste bladder are exhausted. In someembodiments, a portion of the cartridge 1000 can be disposable whileanother portion of the cartridge 1000 is disposable, but lasts longerbefore being discarded. In some embodiments, a portion of the cartridge1000 may not be disposable at all. For example, a portion thereof may beconfigured to be cleaned thoroughly and reused for different patients.Various combinations of disposable and less- or non-disposable portionsare possible.

The cartridge 1000 can be configured for easy replacement. For example,in some embodiments, the cartridge 1000 is designed to have aninstallation time of only minutes. For example, the cartridge can bedesigned to be installed in less than about five minutes, or less thantwo minutes. During installation, various fluid lines contained in thecartridge 1000 can be primed by automatically filling the fluid lineswith saline. The saline can be mixed with detergent powder from thecleaner pouch in order to create a cleaning solution.

The cartridge 1000 can also be designed to have a relatively brief shutdown time. For example, the shut down process can be configured to takeless than about fifteen minutes, or less than about ten minutes, or lessthan about five minutes. The shut down process can include flushing thepatient line; sealing off the insulin pump connection, the saline sourceconnection, and the sample source connection; and taking other steps todecrease the risk that fluids within the used cartridge 1000 will leakafter disconnection from the monitoring device.

Some embodiments of the cartridge 1000 can comprise a flat package tofacilitate packaging, shipping, sterilizing, etc. Advantageously,however, some embodiments can further comprise a hinge or other pivotstructure. Thus, as illustrated, an optical interface portion 1030 canbe pivoted around a pivot structure 1032 to generally align with theother portions of the cartridge 1000. The cartridge can be provided to amedical provider sealed in a removable wrapper, for example.

In some embodiments, the cartridge 1000 is designed to fit withinstandard waste containers found in a hospital, such as a standardbiohazard container. For example, the cartridge 1000 can be less thanone foot long, less than one foot wide, and less than two inches thick.In some embodiments, the cartridge 1000 is designed to withstand asubstantial impact, such as that caused by hitting the ground after afour foot drop, without damage to the housing or internal components. Insome embodiments, the cartridge 1000 is designed to withstandsignificant clamping force applied to its casing. For example, thecartridge 1000 can be built to withstand five pounds per square inch offorce without damage. In some embodiments, the cartridge 1000 can bedesigned to be less sturdy and more biodegradable. In some embodiments,the cartridge 1000 can be formed and configured to withstand more orless than five pounds of force per square inch without damage. In someembodiments, the cartridge 1000 is non pyrogenic and/or latex free.

FIG. 11 illustrates an embodiment of a fluid-routing card 1038 that canbe part of the removable cartridge of FIG. 10. For example, thefluid-routing card 1038 can be located generally within the tubingportion 1008 of the cartridge 1000. The fluid-routing card 1038 cancontain various passages and/or tubes through which fluid can flow asdescribed with respect to FIG. 5 and/or FIG. 6, for example. Thus, theillustrated tube opening openings can be in fluid communication with thefollowing fluidic components, for example:

Tube Opening Reference Numeral Can Be In Fluid Communication With 1142third pump 568 (pump #3) 1144 infusion pump 518 1146 Presx 1148 air pump1150 Vent 1152 detergent (e.g., tergazyme) source or waste tube 1154Presx 1156 detergent (e.g., tergazyme) source or waste tube 1158 wastereceptacle 1160 first pump 522 (pump #1) (e.g., a saline pump) 1162saline source or waste tube 1164 anticoagulant (e.g., heparin) pump (seeFIG. 6) and/or shuttle valve 1166 detergent (e.g., tergazyme) source orwaste tube 1167 Presx 1168 Arrival sensor tube 528 (T4) 1169 tube 536(T2) 1170 Arrival sensor tube 528 (T4) 1171 Arrival sensor tube 528 (T4)1172 anticoagulant (e.g., heparin) pump 1173 T17 (see FIG. 6) 1174Sample cell holder interface tube 582 (N1) 1176 anticoagulant valve tube534 (T3) 1178 Sample cell holder interface tube 584 (N2) 1180 T17 (seeFIG. 6) 1182 anticoagulant valve tube 534 (T3) 1184 Arrival sensor tube528 (T4) 1186 tube 536 (T2) 1188 anticoagulant valve tube 534 (T3) 1190anticoagulant valve tube 534 (T3)

The depicted fluid-routing card 1038 can have additional openings thatallow operative portions of actuators and/or valves to protrude throughthe fluid-routing card 1038 and interface with the tubes.

FIG. 12 illustrates how actuators, which can sandwich the fluid-routingcard 1038 between them, can interface with the fluid-routing card 1038of FIG. 11. Pinch valves 812 can have an actuator portion that protrudesaway from the fluid-routing card 1038 containing a motor. Each motor cancorrespond to a pinch platen 1202, which can be inserted into a pinchplaten receiving hole 1204. Similarly, sensors, such as a bubble sensor1206 can be inserted into receiving holes (e.g., the bubble sensorreceiving hole 1208). Movement of the pinch valves 812 can be detectedby the position sensors 1210.

FIG. 13 illustrates an actuator 808 that is connected to a correspondingsyringe body 810. The actuator 808 is an example of one of the actuators808 that is illustrated in FIG. 8 and in FIG. 9, and the syringe body810 is an example of one of the syringe bodies 810 that are visible inFIG. 8 and in FIG. 9. A ledge portion 1212 of the syringe body 810 canbe engaged (e.g., slid into) a corresponding receiving portion 1214 inthe actuator 808. In some embodiments, the receiving portion 1214 canslide outward to engage the stationary ledge portion 1212 after thedisposable cartridge 804 is in place. Similarly, a receiving tube 1222in the syringe plunger 1223 can be slide onto (or can receive) aprotruding portion 1224 of the actuator 808. The protruding portion 1224can slide along a track 1226 under the influence of a motor inside theactuator 808, thus actuating the syringe plunger 1223 and causing fluidto flow into or out of the syringe tip 1230.

FIG. 14 shows a rear perspective view of internal scaffolding 1231 andthe protruding bodies of some pinch valves 812. The internal scaffolding1231 can be formed from metal and can provide structural rigidity andsupport for other components. The scaffolding 1231 can have holes 1232into which screws can be screwed or other connectors can be inserted. Insome embodiments, a pair of sliding rails 1234 can allow relativemovement between portions of an analyzer. For example, a slidableportion 1236 (which can correspond to the movable portion 706, forexample) can be temporarily slid away from the scaffolding 1231 of amain unit in order to allow an insertable portion (e.g., the cartridge804) to be inserted.

FIG. 15 shows an underneath perspective view of the sample cell holder820, which is attached to the centrifuge interface 1036. The sample cellholder 820 can have an opposite side (see FIG. 17) that allows it toslide into a receiving portion of the centrifuge interface 1036. Thesample cell holder 820 can also have receiving nubs 1512A that provide apathway into a sample cell 1548 held by the sample cell holder 820.Receiving nubs 1512B can provide access to a shunt 1586 (see FIG. 16)inside the sample cell holder 820. The receiving nubs 1512A and 1512Bcan receive and or dock with fluid nipples 1514. The fluid nipples 1514can protrude at an angle from the sample injector 1006, which can inturn protrude from the cartridge 1000 (see FIG. 10). The tubes 1516shown protruding from the other end of the sample injector 1006 can bein fluid communication with the sample cell holder interface tubes 582(N1) and 584 (N2) (see FIG. 5 and FIG. 6), as well as 1074 and 1078 (seeFIG. 11).

FIG. 16 shows a plan view of the sample cell holder 820 with hiddenand/or non-surface portions illustrated using dashed lines. Thereceiving nubs 1512A communicate with passages 1550 inside the samplecell 1548 (which can correspond, for example to the sample cell 548 ofFIG. 5). The passages widen out into a wider portion 1552 thatcorresponds to a window 1556. The window 1556 and the wider portion 1552can be configured to house the sample when radiation is emitted along apathlength that is generally non-parallel to the sample cell 1548. Thewindow 1556 can allow calibration of the instrument with the sample cell1548 in place, even before a sample has arrived in the wider portion1552.

An opposite opening 1530 can provide an alternative optical pathwaybetween a radiation source and a radiation detector (e.g., the radiationsource 826 of FIG. 18) and may be used, for example, for obtaining acalibration measurement of the source and detector without anintervening window or sample. Thus, the opposite opening 1530 can belocated generally at the same radial distance from the axis of rotationas the window 1556.

The receiving nubs 1512B communicate with a shunt passage 1586 insidethe sample cell holder 820 (which can correspond, for example to theshunt 586 of FIG. 5).

Other features of the sample cell holder 820 can provide balancingproperties for even rotation of the sample cell holder 820. For example,the wide trough 1562 and the narrower trough 1564 can be sized orotherwise configured so that the weight and/or mass of the sample cellholder 820 is evenly distributed from left to right in the view of FIG.16, and/or from top to bottom in this view of FIG. 16.

FIG. 17 shows a top perspective view of the centrifuge interface 1036connected to the sample cell holder 820. The centrifuge interface 1036can have a bulkhead 1520 with a rounded slot 1522 into which anactuating portion of a centrifuge can be slid from the side. Thecentrifuge interface 1036 can thus be spun about an axis 1524, alongwith the sample cell holder 820, causing fluid (e.g., whole blood)within the sample cell 1548 to separate into concentric strata,according to relative density of the fluid components (e.g., plasma, redblood cells, buffy coat, etc.), within the sample cell 1548. The samplecell holder 820 can be transparent, or it can at least have transparentportions (e.g., the window 1556 and/or the opposite opening 1530)through which radiation can pass, and which can be aligned with anoptical pathway between a radiation source and a radiation detector(see, e.g., FIG. 20). In addition, a round opening 1530 throughcentrifuge rotor 1520 provides an optical pathway between the radiationsource and radiation detector and may be used, for example, forobtaining a calibration measurement of the source and detector withoutan intervening window or sample.

FIG. 18 shows a perspective view of an example optical system 803. Sucha system can be integrated with other systems as shown in FIG. 9, forexample. The optical system 803 can fill the role of the optical system412, and it can be integrated with and/or adjacent to a fluid system(e.g., the fluid-handling system 404 or the fluid system 801). Thesample cell holder 820 can be seen attached to the centrifuge interface1036, which is in turn connected to, and rotatable by the centrifugemotor 818. A filter wheel housing 1812 is attached to the filter wheelmotor 822 and encloses a filter wheel 1814. A protruding shaft assembly1816 can be connected to the filter wheel 1814. The filter wheel 1814can have multiple filters (see FIG. 19). The radiation source 826 isaligned to transmit radiation through a filter in the filter wheel 1814and then through a portion of the sample cell holder 820. Transmittedand/or reflected and/or scattered radiation can then be detected by aradiation detector.

FIG. 19 shows a view of the filter wheel 1814 when it is not locatedwithin the filter wheel housing 1812 of the optical system 803.Additional features of the protruding shaft assembly 1816 can be seen,along with multiple filters 1820. In some embodiments, the filters 1820can be removably and/or replaceably inserted into the filter wheel 1814.

Spectroscopic System

As described above with reference to FIG. 4, the system 400 comprisesthe optical system 412 for analysis of a fluid sample. In variousembodiments, the optical system 412 comprises one or more opticalcomponents including, for example, a spectrometer, a photometer, areflectometer, or any other suitable device for measuring opticalproperties of the fluid sample. The optical system 412 may perform oneor more optical measurements on the fluid sample including, for example,measurements of transmittance, absorbance, reflectance, scattering,and/or polarization. The optical measurements may be performed in one ormore wavelength ranges including, for example, infrared (IR) and/oroptical wavelengths. As described with reference to FIG. 4 (and furtherdescribed below), the measurements from the optical system 412 arecommunicated to the algorithm processor 416 for analysis. For example,In some embodiments the algorithm processor 416 computes concentrationof analyte(s) (and/or interferent(s)) of interest in the fluid sample.Analytes of interest include, e.g., glucose and lactate in whole bloodor blood plasma.

FIG. 20 schematically illustrates an embodiment of the optical system412 that comprises a spectroscopic analyzer 2010 adapted to measurespectra of a fluid sample such as, for example, blood or blood plasma.The analyzer 2010 comprises an energy source 2012 disposed along anoptical axis X of the analyzer 2010. When activated, the energy source2012 generates an electromagnetic energy beam E, which advances from theenergy source 2012 along the optical axis X. In some embodiments, theenergy source 2012 comprises an infrared energy source, and the energybeam E comprises an infrared beam. In some embodiments, the infraredenergy beam E comprises a mid-infrared energy beam or a near-infraredenergy beam. In some embodiments, the energy beam E can include opticaland/or radio frequency wavelengths.

The energy source 2012 may comprise a broad-band and/or a narrow-bandsource of electromagnetic energy. In some embodiments, the energy source2012 comprises optical elements such as, e.g., filters, collimators,lenses, mirrors, etc., that are adapted to produce a desired energy beamE. For example, in some embodiments, the energy beam E is an infraredbeam in a wavelength range between about 2 μm and 20 μm. In someembodiments, the energy beam E comprises an infrared beam in awavelength range between about 4 μm and 10 μm. In the infraredwavelength range, water generally is the main contributor to the totalabsorption together with features from absorption of other bloodcomponents, particularly in the 6 μm-10 μm range. The 4 μm to 10 μmwavelength band has been found to be advantageous for determiningglucose concentration, because glucose has a strong absorption peakstructure from about 8.5 μm to 10 μm, whereas most other bloodcomponents have a relatively low and flat absorption spectrum in the 8.5μm to 10 μm range. Two exceptions are water and hemoglobin, which areinterferents in this range.

The energy beam E may be temporally modulated to provide increasedsignal-to-noise ratio (S/N) of the measurements provided by the analyzer2010 as further described below. For example, in some embodiments, thebeam E is modulated at a frequency of about 10 Hz or in a range fromabout 1 Hz to about 30 Hz. A suitable energy source 2012 may be anelectrically modulated thin-film thermoresistive element such as theHawkEye IR-50 available from Hawkeye Technologies of Milford, Conn.

As depicted in FIG. 20, the energy beam E propagates along the opticalaxis X and passes through an aperture 2014 and a filter 2015 therebyproviding a filtered energy beam E_(f). The aperture 2014 helpscollimate the energy beam E and can include one or more filters adaptedto reduce the filtering burden of the filter 2015. For example, theaperture 2014 may comprise a broadband filter that substantiallyattenuates beam energy outside a wavelength band between about 4 μm toabout 10 μm. The filter 2015 may comprise a narrow-band filter thatsubstantially attenuates beam energy having wavelengths outside of afilter passband (which may be tunable or user-selectable in someembodiments). The filter passband may be specified by a half-powerbandwidth (“HPBW”). In some embodiments, the filter 2015 may have anHPBW in a range from about 0.1 μm to about 2 μm, or 0.01 μm to about 1μm. In some embodiments, the bandwidths are in a range from about 0.2 μmto 0.5 μm, or 0.1 μm to 0.35 μm. Other filter bandwidths may be used.The filter 2015 may comprise a varying-passband filter, anelectronically tunable filter, a liquid crystal filter, an interferencefilter, and/or a gradient filter. In some embodiments, the filter 2015comprises one or a combination of a grating, a prism, a monochrometer, aFabry-Perot etalon, and/or a polarizer. Other optical elements may beutilized as well.

In the embodiment shown in FIG. 20, the analyzer 2010 comprises a filterwheel assembly 2021 configured to dispose one or more filters 2015 alongthe optical axis X. The filter wheel assembly 2021 comprises a filterwheel 2018, a filter wheel motor 2016, and a position sensor 2020. Thefilter wheel 2018 may be substantially circular and have one or morefilters 2015 or other optical elements (e.g., apertures, gratings,polarizers, mirrors, etc.) disposed around the circumference of thewheel 2018. In some embodiments, the number of filters 2015 in thefilter wheel 2016 may be, for example, 1, 2, 5, 10, 15, 20, 25, or more.The motor 2016 is configured to rotate the filter wheel 2018 to disposea desired filter 2015 (or other optical element) in the energy beam E soas to produce the filtered beam E_(f). In some embodiments, the motor2016 comprises a stepper motor. The position sensor 2020 determines theangular position of the filter wheel 2016, and communicates acorresponding filter wheel position signal to the algorithm processor416, thereby indicating which filter 2015 is in position on the opticalaxis X. In various embodiments, the position sensor 2020 may be amechanical, optical, and/or magnetic encoder. An alternative to thefilter wheel 2018 is a linear filter translated by a motor. The linearfilter can include an array of separate filters or a single filter withproperties that change along a linear dimension.

The filter wheel motor 2016 rotates the filter wheel 2018 to positionthe filters 2015 in the energy beam E to sequentially vary thewavelengths or the wavelength bands used to analyze the fluid sample. Insome embodiments, each individual filter 2015 is disposed in the energybeam E for a dwell time during which optical properties in the passbandof the filter are measured for the sample. The filter wheel motor 2016then rotates the filter wheel 2018 to position another filter 2015 inthe beam E. In some embodiments, 25 narrow-band filters are used in thefilter wheel 2018, and the dwell time is about 2 seconds for each filter2015. A set of optical measurements for all the filters can be taken inabout 2 minutes, including sampling time and filter wheel movement. Insome embodiments, the dwell time may be different for different filters2015, for example, to provide a substantially similar S/N ratio for eachfilter measurement. Accordingly, the filter wheel assembly 2021functions as a varying-passband filter that allows optical properties ofthe sample to be analyzed at a number of wavelengths or wavelength bandsin a sequential manner.

In some embodiments of the analyzer 2010, the filter wheel 2018 includes25 finite-bandwidth infrared filters having a Gaussian transmissionprofile and full-width half-maximum (FWHM) bandwidth of 28 cm⁻¹corresponding to a bandwidth that varies from 0.14 μm at 7.08 μm to 0.28μm at 10 μm. The central wavelength of the filters are, in microns:7.082, 7.158, 7.241, 7.331, 7.424, 7.513, 7.605, 7.704, 7.800, 7.905,8.019, 8.150, 8.271, 8.598, 8.718, 8.834, 8.969, 9.099, 9.217, 9.346,9.461, 9.579, 9.718, 9.862, and 9.990.

With further reference to FIG. 20, the filtered energy beam E_(f)propagates to a beamsplitter 2022 disposed along the optical axis X. Thebeamsplitter 2022 separates the filtered energy beam E_(f) into a samplebeam E_(s) and a reference beam E_(r). The reference beam E_(r)propagates along a minor optical axis Y, which in this embodiment issubstantially orthogonal to the optical axis X. The energies in thesample beam E_(s) and the reference beam E_(r) may comprise any suitablefraction of the energy in the filtered beam E_(f). For example, in someembodiments, the sample beam E_(s) comprises about 80%, and thereference beam E_(r) comprises about 20%, of the filtered beam energyE_(f) A reference detector 2036 is positioned along the minor opticalaxis Y. An optical element 2034, such as a lens, may be used to focus orcollimate the reference beam E_(r) onto the reference detector 2036. Thereference detector 2036 provides a reference signal, which can be usedto monitor fluctuations in the intensity of the energy beam E emitted bythe source 2012. Such fluctuations may be due to drift effects, aging,wear, or other imperfections in the source 2012. The algorithm processor416 may utilize the reference signal to identify changes in propertiesof the sample beam E_(s) that are attributable to changes in theemission from the source 2012 and not to the properties of the fluidsample. By so doing, the analyzer 2010 may advantageously reducepossible sources of error in the calculated properties of the fluidsample (e.g., concentration). In other embodiments of the analyzer 2010,the beamsplitter 2022 is not used, and substantially all of the filteredenergy beam E_(f) propagates to the fluid sample.

As illustrated in FIG. 20, the sample beam E_(s) propagates along theoptical axis X, and a relay lens 2024 transmits the sample beam E_(s)into a sample cell 2048 so that at least a fraction of the sample beamE_(s) is transmitted through at least a portion of the fluid sample inthe sample cell 2048. A sample detector 2030 is positioned along theoptical axis X to measure the sample beam E_(s) that has passed throughthe portion of the fluid sample. An optical element 2028, such as alens, may be used to focus or collimate the sample beam E_(s) onto thesample detector 2030. The sample detector 2030 provides a sample signalthat can be used by the algorithm processor 416 as part of the sampleanalysis.

In the embodiment of the analyzer 2010 shown in FIG. 20, the sample cell2048 is located toward the outer circumference of the centrifuge wheel2050 (which can correspond, for example, to the sample cell holder 820described herein). The sample cell 2048 preferably comprises windowsthat are substantially transmissive to energy in the sample beam E. Forexample, in implementations using mid-infrared energy, the windows maycomprise calcium fluoride. As described herein with reference to FIG. 5,the sample cell 2048 is in fluid communication with an injector systemthat permits filling the sample cell 2048 with a fluid sample (e.g.,whole blood) and flushing the sample cell 2048 (e.g., with saline or adetergent). The injector system may disconnect after filling the samplecell 2048 with the fluid sample to permit free spinning of thecentrifuge wheel 2050.

The centrifuge wheel 2050 can be spun by a centrifuge motor 2026. Insome embodiments of the analyzer 2010, the fluid sample (e.g., a wholeblood sample) is spun at a certain number of revolutions per minute(RPM) for a given length of time to separate blood plasma for spectralanalysis. In some embodiments, the fluid sample is spun at about 7200RPM. In some embodiments, the fluid sample is spun at about 5000 RPM or4500 RPM. In some embodiments, the fluid sample is spun at more than onerate for successive time periods. The length of time can beapproximately 5 minutes. In some embodiments, the length of time isapproximately 2 minutes. In some embodiments, an anti-clotting agentsuch as heparin may be added to the fluid sample before centrifuging toreduce clotting. With reference to FIG. 20, the centrifuge wheel 2050 isrotated to a position where the sample cell 2048 intercepts the samplebeam E_(s), allowing energy to pass through the sample cell 2048 to thesample detector 2030.

The embodiment of the analyzer 2010 illustrated in FIG. 20advantageously permits direct measurement of the concentration ofanalytes in the plasma sample rather than by inference of theconcentration from measurements of a whole blood sample. An additionaladvantage is that relatively small volumes of fluid may bespectroscopically analyzed. For example, in some embodiments the fluidsample volume is between about 1 μL and 80 μL and is about 25 μL in someembodiments. In some embodiments, the sample cell 2048 is disposable andis intended for use with a single patient or for a single measurement.

In some embodiments, the reference detector 2036 and the sample detector2030 comprise broadband pyroelectric detectors. As known in the art,some pyroelectric detectors are sensitive to vibrations. Thus, forexample, the output of a pyroelectric infrared detector is the sum ofthe exposure to infrared radiation and to vibrations of the detector.The sensitivity to vibrations, also known as “microphonics,” canintroduce a noise component to the measurement of the reference andsample energy beams E_(r), E_(s) using some pyroelectric infrareddetectors. Because it may be desirable for the analyzer 2010 to providehigh signal-to-noise ratio measurements, such as, e.g., S/N in excess of100 dB, some embodiments of the analyzer 2010 utilize one or morevibrational noise reduction apparatus or methods. For example, theanalyzer 2010 may be mechanically isolated so that high S/Nspectroscopic measurements can be obtained for vibrations below anacceleration of about 1.5 G.

In some embodiments of the analyzer 2010, vibrational noise can bereduced by using a temporally modulated energy source 2012 combined withan output filter. In some embodiments, the energy source 2012 ismodulated at a known source frequency, and measurements made by thedetectors 2036 and 2030 are filtered using a narrowband filter centeredat the source frequency. For example, in some embodiments, the energyoutput of the source 2012 is sinusoidally modulated at 10 Hz, andoutputs of the detectors 2036 and 2030 are filtered using a narrowbandpass filter of less than about 1 Hz centered at 10 Hz. Accordingly,microphonic signals that are not at 10 Hz are significantly attenuated.In some embodiments, the modulation depth of the energy beam E may begreater than 50% such as, for example, 80%. The duty cycle of the beammay be between about 30% and 70%. The temporal modulation may besinusoidal or any other waveform. In embodiments utilizing temporallymodulated energy sources, detector output may be filtered using asynchronous demodulator and digital filter. The demodulator and filterare software components that may be digitally implemented in a processorsuch as the algorithm processor 416. Synchronous demodulators, coupledwith low pass filters, are often referred to as “lock in amplifiers.”

The analyzer 2010 may also include a vibration sensor 2032 (e.g., one ormore accelerometers) disposed near one (or both) of the detectors 2036and 2030. The output of the vibration sensor 2032 is monitored, andsuitable actions are taken if the measured vibration exceeds a vibrationthreshold. For example, in some embodiments, if the vibration sensor2032 detects above-threshold vibrations, the system discards any ongoingmeasurement and “holds off” on performing further measurements until thevibrations drop below the threshold. Discarded measurements may berepeated after the vibrations drop below the vibration threshold. Insome embodiments, if the duration of the “hold off” is sufficientlylong, the fluid in the sample cell 2030 is flushed, and a new fluidsample is delivered to the cell 2030 for measurement. The vibrationthreshold may be selected so that the error in analyte measurement is atan acceptable level for vibrations below the threshold. In someembodiments, the threshold corresponds to an error in glucoseconcentration of 5 mg/dL. The vibration threshold may be determinedindividually for each filter 2015.

Certain embodiments of the analyzer 2010 include a temperature system(not shown in FIG. 20) for monitoring and/or regulating the temperatureof system components (such as the detectors 2036, 2030) and/or the fluidsample. Such a temperature system can include temperature sensors,thermoelectrical heat pumps (e.g., a Peltier device), and/orthermistors, as well as a control system for monitoring and/orregulating temperature. In some embodiments, the control systemcomprises a proportional-plus-integral-plus-derivative (PID) control.For example, in some embodiments, the temperature system is used toregulate the temperature of the detectors 2030, 2036 to a desiredoperating temperature, such as 35 degrees Celsius.

Optical Measurement

The analyzer 2010 illustrated in FIG. 20 can be used to determineoptical properties of a substance in the sample cell 2048. The substancecan include whole blood, plasma, saline, water, air or other substances.In some embodiments, the optical properties include measurements of anabsorbance, transmittance, and/or optical density in the wavelengthpassbands of some or all of the filters 2015 disposed in the filterwheel 2018. As described above, a measurement cycle comprises disposingone or more filters 2015 in the energy beam E for a dwell time andmeasuring a reference signal with the reference detector 2036 and asample signal with the sample detector 2030. The number of filters 2015used in the measurement cycle will be denoted by N, and each filter 2015passes energy in a passband around a center wavelength λ_(i), where i isan index ranging over the number of filters (e.g., from 1 to N). The setof optical Measurements from the sample detector 2036 in the passbandsof the N filters 2015 provide a wavelength-dependent spectrum of thesubstance in the sample cell 2048. The spectrum will be denoted byC_(s)(λ_(i)), where C_(s) may be a transmittance, absorbance, opticaldensity, or some other measure of an optical property of the substance.In some embodiments, the spectrum is normalized with respect to one ormore of the reference signals measured by the reference detector 2030and/or with respect to spectra of a reference substance (e.g., air orsaline). The measured spectra are communicated to the algorithmprocessor 416 for calculation of the concentration of the analyte(s) ofinterest in the fluid sample.

In some embodiments, the analyzer 2010 performs spectroscopicmeasurements on the fluid sample (known as a “wet” reading) and on oneor more reference samples. For example, an “air” reading occurs when thesample detector 2036 measures the sample signal without the sample cell2048 in place along the optical axis X. (This can occur, for example,when the opposite opening 1530 is aligned, with the optical axis X). A“water” or “saline” reading occurs when the sample cell 2048 is filledwith water or saline, respectively. The algorithm processor 416 may beprogrammed to calculate analyte concentration using a combination ofthese spectral measurements.

In some embodiments, a pathlength corrected spectrum is calculated usingwet, air, and reference readings. For example, the transmittance atwavelength λ_(i), denoted by T_(i), may be calculated according toT_(i)=(S_(i)(wet)/R_(i)(wet))/(S_(i)(air)/R_(i)(air)), where S_(i)denotes the sample signal from the sample detector 2036 and R; denotesthe corresponding reference signal from the reference detector 2030. Insome embodiments, the algorithm processor 416 calculates the opticaldensity, OD_(i), as a logarithm of the transmittance, e.g., according toOD_(i)=−Log(T_(i)). In one implementation, the analyzer 2010 takes a setof wet readings in each of the N filter passbands and then takes a setof air readings in each of the N filter passbands. In other embodiments,the analyzer 2010 may take an air reading before (or after) thecorresponding wet reading.

The optical density OD_(i) is the product of the absorption coefficientat wavelength λ_(i), α_(i), times the pathlength L over which the sampleenergy beam E_(s) interacts with the substance in the sample cell 2048,e.g., OD_(i)=α_(i) L. The absorption coefficient α_(i) of a substancemay be written as the product of an absorptivity per mole times a molarconcentration of the substance. FIG. 20 schematically illustrates thepathlength L of the sample cell 2048. The pathlength L may be determinedfrom spectral measurements made when the sample cell 2048 is filled witha reference substance. For example, because the absorption coefficientfor water (or saline) is known, one or more water (or saline) readingscan be used to determine the pathlength L from measurements of thetransmittance (or optical density) through the cell 2048. In someembodiments, several readings are taken in different wavelengthpassbands, and a curve-fitting procedure is used to estimate a best-fitpathlength L. The pathlength L may be estimated using other methodsincluding, for example, measuring interference fringes of light passingthrough an empty sample cell 2048.

The pathlength L may be used to determine the absorption coefficients ofthe fluid sample at each wavelength. Molar concentration of an analyteof interest can be determined from the absorption coefficient and theknown molar absorptivity of the analyte. In some embodiments, a samplemeasurement cycle comprises a saline reading (at one or morewavelengths), a set of N wet readings (taken, for example, through asample cell 2048 containing saline solution), followed by a set of N airreadings (taken, for example, through the opposite opening 1530). Asdiscussed above, the sample measurement cycle can be performed in agiven length of time that may depend, at least in part, on filter dwelltimes. For example, the measurement cycle may take five minutes when thefilter dwell times are about five seconds. In some embodiments, themeasurement cycle may take about two minutes when the filter dwell timesare about two seconds. After the sample measurement cycle is completed,a detergent cleaner may be flushed through the sample cell 2048 toreduce buildup of organic matter (e.g., proteins) on the windows of thesample cell 2048. The detergent is then flushed to a waste bladder.

In some embodiments, the system stores information related to thespectral measurements so that the information is readily available forrecall by a user. The stored information can includewavelength-dependent spectral measurements (including fluid sample, air,and/or saline readings), computed analyte values, system temperaturesand electrical properties (e.g., voltages and currents), and any otherdata related to use of the system (e.g., system alerts, vibrationreadings, S/N ratios, etc.). The stored information may be retained inthe system for a time period such as, for example, 30 days. After thistime period, the stored information may be communicated to an archivaldata storage system and then deleted from the system. In someembodiments, the stored information is communicated to the archival datastorage system via wired or wireless methods, e.g., over a hospitalinformation system (HIS).

Analyte Analysis

The algorithm processor 416 (FIG. 4) (or any other suitable processor orprocessors) may be configured to receive from the analyzer 2010 thewavelength-dependent optical measurements Cs(λ_(i)) of the fluid sample.In some embodiments, the optical measurements comprise spectra such as,for example, optical densities OD_(i) measured in each of the N filterpassbands centered around wavelengths λ_(i). The optical measurementsCs(λ_(i)) are communicated to the processor 416, which analyzes theoptical measurements to detect and quantify one or more analytes in thepresence of interferents. In some embodiments, one or more poor qualityoptical measurements Cs(λ_(i)) are rejected (e.g., as having a S/N ratiothat is too low), and the analysis performed on the remaining,sufficiently high-quality measurements. In another embodiment,additional optical measurements of the fluid sample are taken by theanalyzer 2010 to replace one or more of the poor quality measurements.

Interferents can comprise components of a material sample being analyzedfor an analyte, where the presence of the interferent affects thequantification of the analyte. Thus, for example, in the spectroscopicanalysis of a sample to determine an analyte concentration, aninterferent could be a compound having spectroscopic features thatoverlap with those of the analyte, in at least a portion of thewavelength range of the measurements. The presence of such aninterferent can introduce errors in the quantification of the analyte.More specifically, the presence of one or more interferents can affectthe sensitivity of a measurement technique to the concentration ofanalytes of interest in a material sample, especially when the system iscalibrated in the absence of, or with an unknown amount of, theinterferent.

Independently of or in combination with the attributes of interferentsdescribed above, interferents can be classified as being endogenous(i.e., originating within the body) or exogenous (i.e., introduced fromor produced outside the body). As an example of these classes ofinterferents, consider the analysis of a blood sample (or a bloodcomponent sample or a blood plasma sample) for the analyte glucose.Endogenous interferents include those blood components having originswithin the body that affect the quantification of glucose, and caninclude water, hemoglobin, blood cells, and any other component thatnaturally occurs in blood. Exogenous interferents include those bloodcomponents having origins outside of the body that affect thequantification of glucose, and can include items administered to aperson, such as medicaments, drugs, foods or herbs, whether administeredorally, intravenously, topically, etc.

Independently of or in combination with the attributes of interferentsdescribed above, interferents can comprise components which arepossibly, but not necessarily, present in the sample type underanalysis. In the example of analyzing samples of blood or blood plasmadrawn from patients who are receiving medical treatment, a medicamentsuch as acetaminophen is possibly, but not necessarily, present in thissample type. In contrast, water is necessarily present in such blood orplasma samples.

Certain disclosed analysis methods are particularly effective if eachanalyte and interferent has a characteristic signature in themeasurement (e.g., a characteristic spectroscopic feature), and if themeasurement is approximately affine (e.g., includes a linear term and anoffset) with respect to the concentration of each analyte andinterferent. In such methods, a calibration process is used to determinea set of one or more calibration coefficients and a set of one or moreoptional offset values that permit the quantitative estimation of ananalyte. For example, the calibration coefficients and the offsets maybe used to calculate an analyte concentration from spectroscopicmeasurements of a material sample (e.g., the concentration of glucose inblood plasma). In some of these methods, the concentration of theanalyte is estimated by multiplying the calibration coefficient by ameasurement value (e.g., an optical density) to estimate theconcentration of the analyte. Both the calibration coefficient andmeasurement can comprise arrays of numbers. For example, in someembodiments, the measurement comprises spectra C_(s)(λ_(i)) measured atthe wavelengths λ_(i), and the calibration coefficient and optionaloffset comprise an array of values corresponding to each wavelengthλ_(i). In some embodiments, as further described below, a hybrid linearanalysis (HLA) technique is used to estimate analyte concentration inthe presence of a set of interferents, while retaining a high degree ofsensitivity to the desired analyte. The data used to accommodate the setof possible interferents can include (a) signatures of each of themembers of the family of potential additional substances and (b) atypical quantitative level at which each additional substance, ifpresent, is likely to appear. In some embodiments, the calibrationcoefficient (and optional offset) are adjusted to minimize or reduce thesensitivity of the calibration to the presence of interferents that areidentified as possibly being present in the fluid sample.

In some embodiments, the analyte analysis method uses a set of trainingspectra each having known analyte concentration and produces acalibration that minimizes the variation in estimated analyteconcentration with interferent concentration. The resulting calibrationcoefficient indicates sensitivity of the measurement to analyteconcentration. The training spectra need not include a spectrum from theindividual whose analyte concentration is to be determined. That is, theterm “training” when used in reference to the disclosed methods does notrequire training using measurements from the individual whose analyteconcentration will be estimated (e.g., by analyzing a bodily fluidsample drawn from the individual).

Several terms are used herein to describe the analyte analysis process.The term “Sample Population” is a broad term and includes, withoutlimitation, a large number of samples having measurements that are usedin the computation of calibration values (e.g., calibration coefficientsand optional offsets). In some embodiments, the term Sample Populationcomprises measurements (such as, e.g., spectra) from individuals and maycomprise one or more analyte measurements determined from those sameindividuals. Additional demographic information may be available for theindividuals whose sample measurements are included in the SamplePopulation. For an embodiment involving the spectroscopic determinationof glucose concentration, the Sample Population measurements may includea spectrum (measurement) and a glucose concentration (analytemeasurement).

Various embodiments of Sample Populations may be used in variousembodiments of the systems and methods described herein. Severalexamples of Sample Populations will now be described. These examples areintended to illustrate certain aspects of possible Sample Populationembodiments but are not intended to limit the types of SamplePopulations that may be generated. In certain embodiments, a SamplePopulation may include samples from one or more of the example SamplePopulations described below.

In some embodiments of the systems and methods described herein, one ormore Sample Populations are included in a “Population Database.” ThePopulation Database may be implemented and/or stored on acomputer-readable medium. In certain embodiments, the systems andmethods may access the Population Database using wired and/or wirelesstechniques. Certain embodiments may utilize several different PopulationDatabases that are accessible locally and/or remotely. In someembodiments, the Population Database includes one or more of the exampleSample Populations described below. In some embodiments, two or moredatabases can be combined into a single database, and in otherembodiments, any one database can be divided into multiple databases.

An example Sample Population may comprise samples from individualsbelonging to one or more demographic groups including, for example,ethnicity, nationality, gender, age, etc. Demographic groups may beestablished for any suitable set of one or more distinctive factors forthe group including, for example, medical, cultural, behavioral,biological, geographical, religious, and genealogical traits. Forexample, in certain embodiments, a Sample Population includes samplesfrom individuals from a specific ethnic group (e.g., Caucasians,Hispanics, Asians, African Americans, etc.). In another embodiment, aSample Population includes samples from individuals of a specific genderor a specific race. In some embodiments, a Sample Population includessamples from individuals belonging to more than one demographic group(e.g., samples from Caucasian women).

Another example Sample Population can comprise samples from individualshaving one or more medical conditions. For example, a Sample Populationmay include samples from individuals who are healthy and unmedicated(sometimes referred to as a Normal Population). In some embodiments, theSample Population includes samples from individuals having one or morehealth conditions (e.g., diabetes). In some embodiments, the SamplePopulation includes samples from individuals taking one or moremedications. In certain embodiments, Sample Population includes samplesfrom individuals diagnosed to have a certain medical condition or fromindividuals being treated for certain medical conditions or somecombination thereof. The Sample Population may include samples fromindividuals such as, for example, ICU patients, maternity patients, andso forth.

An example Sample Population may comprise samples that have the sameinterferent or the same type of interferents. In some embodiments, aSample Population can comprise multiple samples, all lacking aninterferent or a type of interferent. For example, a Sample Populationmay comprise samples that have no exogenous interferents, that have oneor more exogenous interferents of either known or unknown concentration,and so forth. The number of interferents in a sample depends on themeasurement and analyte(s) of interest, and may number, in general, fromzero to a very large number (e.g., greater than 300). All of theinterferents typically are not expected to be present in a particularmaterial sample, and in many cases, a smaller number of interferents(e.g., 0, 1, 2, 5, 10, 15, 20, or 25) may be used in an analysis. Incertain embodiments, the number of interferents used in the analysis isless than or equal to the number of wavelength-dependent measurements Nin the spectrum Cs(λ_(i)).

Certain embodiments of the systems and methods described herein arecapable of analyzing a material sample using one or more SamplePopulations (e.g., accessed from the Population Database). Certain suchembodiments may use information regarding some or all of theinterferents which may or may not be present in the material sample. Insome embodiments, a list of one or more possible interferents, referredto herein as forming a “Library of Interferents,” can be compiled. Eachinterferent in the Library can be referred to as a “LibraryInterferent.” The Library Interferents may include exogenousinterferents and endogenous interferents that may be present in amaterial sample. For example, an interferent may be present due to amedical condition causing abnormally high concentrations of theexogenous and endogenous interferents. In some embodiments, the Libraryof Interferents may not include one or more interferents that are knownto be present in all samples. Thus, for example, water, which is aglucose interferent for many spectroscopic measurements, may not beincluded in the Library of Interferents. In certain embodiments, thesystems and methods use samples in the Sample Population to traincalibration methods.

The material sample being measured, for example a fluid sample in thesample cell 2048, may also include one or more Library Interferentswhich may include, but is not limited to, an exogenous interferent or anendogenous interferent. Examples of exogenous interferent can includemedications, and examples of endogenous interferents can include urea inpersons suffering from renal failure. In addition to componentsnaturally found in the blood, the ingestion or injection of somemedicines or illicit drugs can result in very high and rapidly changingconcentrations of exogenous interferents.

In some embodiments, measurements of a material sample (e.g., a bodilyfluid sample), samples in a Sample Population, and the LibraryInterferents comprise spectra (e.g., infrared spectra). The spectraobtained from a sample and/or an interferent may be temperaturedependent. In some embodiments, it may be beneficial to calibrate fortemperatures of the individual samples in the Sample Population or theinterferents in the Library of Interferents. In some embodiments, atemperature calibration procedure is used to generate a temperaturecalibration factor that substantially accounts for the sampletemperature. For example, the sample temperature can be measured, andthe temperature calibration factor can be applied to the SamplePopulation and/or the Library Interferent spectral data. In someembodiments, a water or saline spectrum is subtracted from the samplespectrum to account for temperature effects of water in the sample.

In other embodiments, temperature calibration may not be used. Forexample, if Library Interferent spectra, Sample Population spectra, andsample spectra are obtained at approximately the same temperature, anerror in a predicted analyte concentration may be within an acceptabletolerance. If the temperature at which a material sample spectrum ismeasured is within, or near, a temperature range (e.g., several degreesCelsius) at which the plurality of Sample Population spectra areobtained, then some analysis methods may be relatively insensitive totemperature variations. Temperature calibration may optionally be usedin such analysis methods.

Systems and Methods for Estimating Analyte Concentration in the Presenceof Interferents

FIG. 21 is a flowchart that schematically illustrates an embodiment of amethod 2100 for estimating the concentration of an analyte in thepresence of interferents. In block 2110, a measurement of a sample isobtained, and in block 2120 data relating to the obtained measurement isanalyzed to identify possible interferents to the analyte. In block2130, a model is generated for predicting the analyte concentration inthe presence of the identified possible interferents, and in block 2140the model is used to estimate the analyte concentration in the samplefrom the measurement. In certain embodiments of the method 2100, themodel generated in block 2130 is selected to reduce or minimize theeffect of identified interferents that are not present in a generalpopulation of which the sample is a member.

An example embodiment of the method 2100 of FIG. 21 for thedetermination of an analyte (e.g., glucose) in a blood sample will nowbe described. This example embodiment is intended to illustrate variousaspects of the method 2100 but is not intended as a limitation on thescope of the method 2100 or on the range of possible analytes. In thisexample, the sample measurement in block 2110 is an absorption spectrum,Cs(X₁), of a measurement sample S that has, in general, one analyte ofinterest, glucose, and one or more interferents.

In block 2120, a statistical comparison of the absorption spectrum ofthe sample S with a spectrum of the Sample Population and combinationsof individual Library Interferent spectra is performed. The statisticalcomparison provides a list of Library Interferents that are possiblycontained in sample S and can include either no Library Interferents orone or more Library Interferents. In this example, in block 2130, one ormore sets of spectra are generated from spectra of the Sample Populationand their respective known analyte concentrations and known spectra ofthe Library Interferents identified in block 2120. In block 2130, thegenerated spectra are used to calculate a model for predicting theanalyte concentration from the obtained measurement. In someembodiments, the model comprises one or more calibration coefficientsκ(λ_(i)) that can be used with the sample measurements Cs(λ_(i)) toprovide an estimate of the analyte concentration, g_(est). In block2140, the estimated analyte concentration is determined form the modelgenerated in block 2130. For example, in some embodiments of HLA, theestimated analyte concentration is calculated according to a linearformula: g_(est)=κ(λ_(i))·C_(s)(λ_(i)). Because the absorptionmeasurements and calibration coefficients may represent arrays ofnumbers, the multiplication operation indicated in the preceding formulamay comprise a sum of the products of the measurements and coefficients(e.g., an inner product or a matrix product). In some embodiments, thecalibration coefficient is determined so as to have reduced or minimalsensitivity to the presence of the identified Library Interferents.

An example embodiment of block 2120 of the method 2100 will now bedescribed with reference to FIG. 22. In this example, block 2120includes forming a statistical Sample Population model (block 2210),assembling a library of interferent data (block 2220), assembling allsubsets of size K of the library interferents (block 2225), comparingthe obtained measurement and statistical Sample Population model withdata for each set of interferents from an interferent library (block2230), performing a statistical test for the presence of eachinterferent from the interferent library (block 2240), and identifyingpossible interferents that pass the statistical test (block 2250). Thesize K of the subsets may be an integer such as, for example, 1, 2, 3,4, 5, 6, 10, 16, or more. The acts of block 2220 can be performed onceor can be updated as necessary. In certain embodiments, the acts ofblocks 2230, 2240, and 2250 are performed sequentially for all subsetsof Library Interferents that pass the statistical test (block 2240). Inthis example, in block 2210, a Sample Population Database is formed thatincludes a statistically large Sample Population of individual spectrataken over the same wavelength range as the sample spectrum,C_(s)(λ_(i)). The Database also includes an analyte concentrationcorresponding to each spectrum. For example, if there are P SamplePopulation spectra, then the spectra in the Database can be representedas C={C₁, C₂, . . . , C_(P)}, and the analyte concentrationcorresponding to each spectrum can be represented as g={g₁, g₂, . . . ,g_(P)}. In some embodiments, the Sample Population does not have any ofthe Library Interferents present, and the material sample hasinterferents contained in the Sample Population and one or more of theLibrary Interferents.

In some embodiments of block 2210, the statistical sample modelcomprises a mean spectrum and a covariance matrix calculated for theSample Population. For example, if each spectrum measured at Nwavelengths λ_(i) is represented by an N×1 array, C, then the meanspectrum, μ, is an N×1 array having values at each wavelength averagedover the range of spectra in the Sample Population. The covariancematrix, V, is calculated as the expected value of the deviation betweenC and μ and can be written as V=E((C−μ) (C−μ)^(T)) where E(·) representsthe expected value and the superscript T denotes transpose. In otherembodiments, additional statistical parameters may be included in thestatistical model of the Sample Population spectra.

Additionally, a Library of Interferents may be assembled in block 2220.A number of possible interferents can be identified, for example, as alist of possible medications or foods that might be ingested by thepopulation of patients at issue. Spectra of these interferents can beobtained, and a range of expected interferent concentrations in theblood, or other expected sample material, can be estimated. In certainembodiments, the Library of Interferents includes, for each of “M”interferents, the absorption spectrum normalized to unit interferentconcentration of each interferent, IF={IF₁, IF₂, . . . , IF_(M)}, and arange of concentrations for each interferent from Tmax={Tmax₁, Tmax₂, .. . , Tmax_(M)) to Tmin={Tmin₁, Tmin₂, . . . , Tmin_(M)). Information inthe Library may be assembled once and accessed as needed. For example,the Library and the statistical model of the Sample Population may bestored in a storage device associated with the algorithm processor 416(see, FIG. 4).

Continuing in block 2225, the algorithm processor 416 assembles one ormore subsets comprising a number K of spectra taken from the Library ofInterferents. The number K may be an integer such as, for example, 1, 2,3, 4, 5, 6, 10, 16, or more. In some embodiments, the subsets compriseall combinations of the M Library spectra taken K at a time. In theseembodiments, the number of subsets having K spectra is M!/(K!(M−K)!),where ! represents the factorial function.

Continuing in block 2230, the obtained measurement data (e.g., thesample spectrum) and the statistical Sample Population model (e.g., themean spectrum and the covariance matrix) are compared with data for eachsubset of interferents determined in block 2225 in order to determinethe presence of possible interferents in the sample (block 2240). Insome embodiments, the statistical test for the presence of aninterferent subset in block 2240 comprises determining theconcentrations of each subset of interferences that minimize astatistical measure of “distance” between a modified spectrum of thematerial sample and the statistical model of the Sample Population(e.g., the mean μ and the covariance V). The term “concentration” usedin this context refers to a computed value, and, in some embodiments,that computed value may not correspond to an actual concentration. Theconcentrations may be calculated numerically. In some embodiments, theconcentrations are calculated by algebraically solving a set of linearequations. The statistical measure of distance may comprise thewell-known Mahalanobis distance (or square of the Mahalanobis distance)and/or some other suitable statistical distance metric (e.g.,Hotelling's T-square statistic). In certain implementations, themodified spectrum is given by C′_(s)(T)=C_(s)−IF·T where T=(T₁, T₂, . .. T_(K))^(T) is a K-dimensional column vector of interferentconcentrations and IF={IF₁, IF₂, . . . IF_(K)} represents the Kinterferent absorption spectra of the subset. In some embodiments,concentration of the i^(th) interferent is assumed to be in a range froma minimum value, Tmin_(i), to a maximum value, Tmax_(i), The value ofTmin_(i), may be zero, or may be a value between zero and Tmax_(i), suchas a fraction of Tmax_(i), or may be a negative value. Negative valuesrepresent interferent concentrations that are smaller than baselineinterferent values in the Sample Population.

In block 2250, a list of a number N_(S) of possible interferent subsetsξ may be identified as the particular subsets that pass one or morestatistical tests (in block 2240) for being present in the materialsample. One or more statistical tests may be used, alone or incombination, to identify the possible interferents. For example, if astatistical test indicates that an i^(th) interferent is present in aconcentration outside the range Tmin_(i) to Tmax_(i), then this resultmay be used to exclude the i^(th) interferent from the list of possibleinterferents. In some embodiments, only the single most probableinterferent subset is included on the list, for example, the subsethaving the smallest statistical distance (e.g., Mahalanobis distance).In an embodiment, the list includes the subsets ξ having statisticaldistances smaller than a threshold value. In certain embodiments, thelist includes a number N_(S) of subsets having the smallest statisticaldistances, e.g., the list comprises the “best” candidate subsets. Thenumber N_(S) may be any suitable integer such as 10, 20, 50, 100, 200,or more. An advantage of selecting the “best” N_(S) subsets is reducedcomputational burden on the algorithm processor 416. In someembodiments, the list includes all the Library Interferents. In certainsuch embodiments, the list is selected to comprise combinations of theN_(S) subsets taken L at a time. For example, in some embodiments, pairsof subsets are taken (e.g., L=2). An advantage of selecting pairs ofsubsets is that pairing captures the most likely combinations ofinterferents and the “best” candidates are included multiple times inthe list of possible interferents. In embodiments in which combinationsof L subsets are selected, the number of combinations of subsets in thelist of possible interferent subsets is N_(S)!/(L!(N_(S)−L)!).

In other embodiments, the list of possible interferent subsets ξ isdetermined using a combination of some or all of the above criteria. Inanother embodiment, the list of possible interferent subsets includeseach of the subsets assembled in block 2225. Many selection criteria arepossible for the list of possible interferent subsets ξ.

Returning to FIG. 21, the method 2100 continues in block 2130 whereanalyte concentration is estimated in the presence of the possibleinterferent subsets determined in block 2250. FIG. 23 is a flowchartthat schematically illustrates an example embodiment of the acts ofblock 2130. In block 2310, synthesized Sample Population measurementsare generated to form an Interferent Enhanced Spectral Database (IESD).In block 2360, the IESD and known analyte concentrations are used togenerate calibration coefficients for the selected interferent subset.As indicated in block 2365, blocks 2310 and 2360 may be repeated foreach interferent subset identified in the list of possible interferentsubsets (e.g., in block 2250 of FIG. 22). In this example embodiment,when all the interferent subsets have been processed, the methodcontinues in block 2370, wherein an average calibration coefficient isapplied to the measured spectra to determine a set of analyteconcentrations.

In one example embodiment for block 2310, synthesized Sample Populationspectra are generated by adding random concentrations of eachinterferent in one of the possible interferent subsets These spectra arereferred to herein as an Interferent-Enhanced Spectral Database or IESD.In one example method, the IESD is formed as follows. A plurality ofRandomly-Scaled Single Interferent Spectra (RSIS) are formed for eachinterferent in the interferent subset ξ. Each RSIS is formed bycombinations of the interferent having spectrum IF multiplied by themaximum concentration Tmax, which is scaled by a random factor betweenzero and one. In certain embodiments, the scaling places the maximumconcentration at the 95^(th) percentile of a log-normal distribution inorder to generate a wide range of concentrations. In some embodiments,the log-normal distribution has a standard deviation equal to half ofits mean value.

In this example method, individual RSIS are then combined independentlyand in random combinations to form a large family of CombinationInterferent Spectra (CIS), with each spectrum in the CIS comprising arandom combination of RSIS, selected from the full set of identifiedLibrary Interferents. An advantage of this method of selecting the CISis that it produces adequate variability with respect to eachinterferent, independently across separate interferents.

The CIS and replicates of the Sample Population spectra are combined toform the IESD. Since the interferent spectra and the Sample Populationspectra may have been obtained from measurements having differentoptical pathlengths, the CIS may be scaled to the same pathlength as theSample Population spectra. The Sample Population Database is thenreplicated R times, where R depends on factors including the size of theDatabase and the number of interferents. The IESD includes R copies ofeach of the Sample Population spectra, where one copy is the originalSample Population Data, and the remaining R-1 copies each have onerandomly chosen CIS spectra added. Accordingly, each of the IESD spectrahas an associated analyte concentration from the Sample Populationspectra used to form the particular IESD spectrum. In some embodiments,a 10-fold replication of the Sample Population Database is used for 130Sample Population spectra obtained from 58 different individuals and 18Library Interferents. A smaller replication factor may be used if thereis greater spectral variety among the Library Interferent spectra, and alarger replication factor may be used if there is a greater number ofLibrary Interferents.

After the IESD is generated in block 2310, in block 2360, the IESDspectra and the known, random concentrations of the subset interferentsare used to generate a calibration coefficient for estimating theanalyte concentration from a sample measurement. The calibrationcoefficient is calculated in some embodiments using a hybrid linearanalysis (HLA) technique. In certain embodiments, the HLA technique usesa reference analyte spectrum to construct a set of spectra that are freeof the desired analyte, projecting the analyte's spectrum orthogonallyaway from the space spanned by the analyte-free calibration spectra, andnormalizing the result to produce a unit response. Further descriptionof embodiments of HLA techniques may be found in, for example,“Measurement of Analytes in Human Serum and Whole Blood Samples byNear-Infrared Raman Spectroscopy,” Chapter 4, Andrew J. Berger, Ph. D.thesis, Massachusetts Institute of Technology, 1998, and “An EnhancedAlgorithm for Linear Multivariate Calibration,” by Andrew J. Berger, etal., Analytical Chemistry, Vol. 70, No. 3, Feb. 1, 1998, pp. 623-627,the entirety of each of which is hereby incorporated by referenceherein. In other embodiments, the calibration coefficients may becalculated using other techniques including, for example, regressiontechniques such as, for example, ordinary least squares (OLS), partialleast squares (PLS), and/or principal component analysis.

In block 2365, the processor 416 determines whether additionalinterferent subsets ξ remain in the list of possible interferentsubsets. If another subset is present in the list, the acts in blocks2310-2360 are repeated for the next subset of interferents usingdifferent random concentrations. In some embodiments, blocks 2310-2360are performed for only the most probable subset on the list.

The calibration coefficient determined in block 2360 corresponds to asingle interferent subset ξ from the list of possible interferentsubsets and is denoted herein as a single-interferent-subset calibrationcoefficient κ_(avg)(ξ). In this example method, after all subsets ξ havebeen processed, the method continues in block 2370, in which thesingle-interferent-subset calibration coefficient is applied to themeasured spectra C_(s) to determine an estimated,single-interferent-subset analyte concentration, g(ξ)=κ_(avg)(ξ)·C_(s),for the interferent subset ξ. The set of the estimated,single-interferent-subset analyte concentrations g(ξ) for all subsets inthe list may be assembled into an array of single-interferent-subsetconcentrations. As noted above, in some embodiments the blocks 2310-2370are performed once for the most probable single-interferent-subset onthe list (e.g., the array of single-interferent analyte concentrationshas a single member).

Returning to block 2140 of FIG. 21, the array ofsingle-interferent-subset concentrations, g(ξ) is combined to determinean estimated analyte concentration, g_(est), for the material sample. Incertain embodiments, a weighting function p(ξ) is determined for each ofthe interferent subsets ξ on the list of possible interferent subsets.The weighting functions may be normalized such that Σp(ξ)=1, where thesum is over all subsets ξ that have been processed from the list ofpossible interferent subsets. In some embodiments, the weightingfunctions can be related to the minimum Mahalanobis distance or anoptimal concentration. In certain embodiments, the weighting functionp(ξ) for each subset ξ, is selected to be a constant, e.g., 1/N_(S)where N_(S) is the number of subsets processed from the list of possibleinterferent subsets. In other embodiments, other weighting functionsp(ξ) can be selected.

In certain embodiments, the estimated analyte concentration, g_(est), isdetermined (in block 2140) by combining the single-interferent-subsetestimates, g(ξ) and the weighting functions, p(ξ), to generate anaverage analyte concentration. The average concentration may be computedaccording to g_(est)=Σg(ξ) p(ξ) where the sum is over the interferentsubsets processed from the list of possible interferent subsets. In someembodiments, the weighting function p(ξ) is a constant value for eachsubset (e.g., a standard arithmetic average is used for determiningaverage analyte concentration). By testing the above described examplemethod on simulated data, it has been found that the average analyteconcentration advantageously has errors that may be reduced incomparison to other methods (e.g., methods using only a single mostprobable interferent).

Although the flowchart in FIG. 21 schematically illustrates anembodiment of the method 2100 performed with reference to the blocks2110-2140 described herein, in other embodiments, the method 2100 can beperformed differently. For example, some or all of the blocks 2110-2140can be combined, performed in a different order than shown, and/or thefunctions of particular blocks may be reallocated to other blocks and/orto different blocks. Embodiments of the method 2100 may utilizedifferent blocks than are shown in FIG. 21.

For example, in some embodiments of the method 2100, the calibrationcoefficient is computed without synthesizing spectra and/or partitioningthe data into calibration sets and test sets. Such embodiments arereferred to herein as “Parameter-Free Interferent Rejection” (PFIR)methods. In one example embodiment using PFIR, for each of the possibleinterferent subsets ξ, the following calculations may be performed tocompute an estimate of a calibration coefficient for each subset ξ. Anaverage concentration may be estimated according to g_(est)=Σg(ξ) p(ξ),where the sum is over the interferent subsets processed from the list ofpossible interferent subsets.

An example of an alternative embodiment of block 2130 includes thefollowing steps and calculations.

Step 1: For a subset's N_(IF) interferents, form a scaled interferentspectra matrix. In certain embodiments, the scaled interferent spectramatrix is the product of an interferent spectral matrix, IF, multipliedby an interferent concentration matrix, T_(max), and can be written as:IF T_(max). In certain such embodiments, the interferent concentrationmatrix T_(max) is a diagonal matrix having entries given by the maximumplasma concentrations for the various interferents.

Step 2: Calculate a covariance for the interferent component. If Xdenotes the IESD, the covariance of X, cov(X), is defined as theexpectation E((X−mean(X))(X−mean(X))^(T)) and iscov(X)≈XX ^(T)/(N−1)−mean(X)mean(X)^(T).As described above, the IESD (e.g., X) is obtained as a combination ofSample Population Spectra, C, with Combination Interferent Spectra(CIS): X_(j)=C_(j)+IF_(j)ξ_(j), therefore the covariance is:cov(X)≈CC ^(T)/(N−1)+IFΞΞ ^(T) IF ^(T)/(N−1)−mean(X)mean(X)^(T),which can be written as,cov(X)≈cov(C)+IF cov(Ξ)IF ^(T).If the weights in the weighting matrix Ξ are independent and identicallydistributed, the covariance of Ξ, cov(Ξ), is a diagonal matrix havingalong the diagonal the variance, v, of the samples in Ξ. The lastequation may be written ascov(X)≈V ₀ +vΦ,where V₀ is the covariance of the original sample population and Φ isthe covariance of the IF spectral set.

Step 3: The group's covariance may be at least partially corrected forthe presence of a single replicate of the Sample Population spectra withthe IESD as formed from N_(IF) replicates of the Sample PopulationSpectra with Combined Interferent Spectra. This partial correction maybe achieved by multiplying the second term in the covariance formulagiven above by a correction factor ρ:V=V ₀ +ρvΦwhere ρ is a scalar weighting function that depends on the number ofinterferents in the group. In some embodiments, the scalar weightingfunction is ρ=N_(IF)/(N_(IF)+1). In certain embodiments, the variance vof the weights is assumed to be the variance of a log-normal randomvariable having a 95th percentile at a value of 1.0, and a standarddeviation equal to half of the mean value.

Step 4: The eigenvectors and the corresponding eigenvalues of thecovariance matrix V are determined using any suitable linear algebraicmethods. The number of eigenvectors (and eigenvalues) is equal to thenumber of wavelengths L in the spectral measurements. The eigenvectorsmay be sorted based on decreasing order of their correspondingeigenvalues.

Step 5: The matrix of eigenvectors is decomposed so as to provide anorthogonal matrix Q. For example, in some embodiments, aQR-decomposition is performed, thereby yielding the matrix Q havingorthonormal columns and rows.

Step 6: The following matrix operations are performed on the orthogonalmatrix Q. For n=2 to L−1, the product P^(∥) _(n)=Q(:,1:n) Q(:,1:n)^(T)is calculated, where Q(:,1:n) denotes the submatrix comprising the firstn columns of the full matrix Q. The orthogonal projection, P^(⊥) _(n),away from the space spanned by Q(:,1:n) is determined by subtractingP^(∥) _(n) from the L×L identity matrix I. The n^(th) calibration vectoris then determined from κ_(n)=P^(⊥) _(n) α_(X)/α_(X) ^(T)P^(⊥) _(n)α_(X), and the n^(th) error variance E_(n) is determined as theprojection of the full covariance V onto the subspace spanned by κ_(n)as follows: E_(n)=κ_(n) ^(T)V κ_(n).

The steps 4-6 of this example are an embodiment of the HLA technique.

In some embodiments, the calibration coefficient κ is selected as thecalibration vector corresponding to the minimum error variance E_(n).Thus, for example, the average group calibration coefficient κ may befound by searching among all the error variances for the error varianceE_(n) that has the minimum value. The calibration coefficient is thenselected as the n^(th) calibration vector κ_(n) corresponding to theminimum error variance E_(n). In other embodiments, the calibrationcoefficient is determined by averaging some or all of the calibrationvectors κ_(n).

EXAMPLES OF ALGORITHM RESULTS AND EFFECTS OF SAMPLE POPULATION

Embodiments of the above-described methods have been used to estimateblood plasma glucose concentrations in humans. Four example experimentswill now be described. The population of individuals from whom sampleswere obtained for analysis (estimation of glucose concentration) will bereferred to as the “target population.” Infrared spectra obtained fromthe target population will be referred to as the “target spectra.” Inthe four example experiments, the target population included 41intensive care unit (ICU) patients. Fifty-five samples were obtainedfrom the target population.

Example Experiment 1

In this example experiment, a partial least squares (PLS) regressionmethod was applied to the infrared target spectra of the targetpatients' blood plasma to obtain the glucose estimates. In exampleexperiment 1, estimated glucose concentration was not corrected foreffects of interferents. The Sample Population used for the analysisincluded infrared spectra and independently measured glucoseconcentrations for 92 individuals selected from the general population.This Sample Population will be referred to as a “Normal Population.”

Example Experiment 2

In example experiment 2, an embodiment of the Parameter-Free InterferentRejection (PFIR) method was used to estimate glucose concentration forthe same target population of patients in example experiment 1. TheSample Population was the Normal Population. In this example,calibration for Library Interferents was applied to the measured targetspectra. The Library of Interferents included spectra of the 59substances listed below:

Acetylsalicylic Acid Ampicillin Sulbactam Azithromycin AztreonamBacitracin Benzyl Alcohol Calcium Chloride Calcium Gluconate CefazolinCefoparazone Cefotaxime Sodium Ceftazidime Ceftriaxone D_SorbitolDextran Ertapenem Ethanol Ethosuximide Glycerol Heparin Hetastarch HumanAlbumin Hydroxy Butyric Acid Imipenem Cilastatin Iohexol L_ArginineLactate Sodium Magnesium Sulfate Maltose Mannitol Meropenem OxylatePotassium Phenytoin Phosphates Potassium Piperacillin PiperacillinTazobactam PlasmaLyteA Procaine HCl Propylene Glycol PyrazinamidePyruvate Sodium Pyruvic Acid Salicylate Sodium Sodium Acetate SodiumBicarbonate Sodium Chloride Sodium Citrate Sodium ThiosulfateSulfadiazine Urea Uric Acid Voriconazole Xylitol Xylose PC 1 of Salinecovariance PC 2 of Saline covariance PC 3 of Saline covariance PC 4 ofSaline covariance ICU/Normal difference spectrum

In some embodiments, the calibration data set is determined according totwo criteria: the calibration method itself (e.g., HLA, PLS, OLS, PFIR)and the intended application of the method. The calibration data set maycomprise spectra and corresponding analyte levels derived from a set ofplasma samples from the Sample Population. In some embodiments, e.g.,those where an HLA calibration method is used, the calibration data setmay also include spectra of the analyte of interest.

In the example experiments 1 and 2, the Sample Population was the NormalPopulation. Thus, samples were drawn from a population of normalindividuals who did not have identifiable medical conditions that mightaffect the spectra of their plasma samples. For example, the sampleplasma spectra typically did not show effects of high levels ofmedications or other substances (e.g., ethanol), or effects of chemicalsthat are indicative of kidney or liver malfunction.

In some embodiments, an analysis method may calibrate for deviationsfrom the distribution defined by the calibration plasma spectra byidentifying a “base” set of interferent spectra likely to be responsiblefor the deviation. The analysis method may then recalibrate with respectto an enhanced spectral data set. In some embodiments, the enhancementcan be achieved by including the identified interferent spectra into thecalibration plasma spectra. When it is anticipated that the targetpopulation may have been administered significant amounts of substancesnot present in the samples of the calibration set, or when the targetpopulation have many distinct interferents, estimation of theinterferents present in the target spectrum may be subject to a largedegree of uncertainty. In some cases, this may cause analyte estimationto be subject to errors.

Accordingly, in certain embodiments, the calibration data set may beenhanced beyond the base of “normal” samples to include a population ofsamples intended to be more representative of the target population. Theenhancement of the calibration set may be generated, in someembodiments, by including samples from a sufficiently diverse range ofindividuals in order to represent the range of likely interferents (bothin type and in concentration) and/or the normal variability inunderlying plasma characteristics. The enhancement may, additionally oralternatively, be generated by synthesizing interferent spectra having arange of concentrations as described above (see, e.g., discussion ofblock 2310 in FIG. 23). Using the enhanced calibration set may reducethe error in estimating the analyte concentration in the target spectra.

Example Experiments 3 and 4

Example experiments 3 and 4 use the analysis methods of exampleexperiments 1 and 2, respectively (PLS without interferent correctionand PFIR with interferent correction). However, example experiments 3and 4 use a Sample Population having blood plasma spectralcharacteristics different from the Normal Population used in exampleexperiments 1 and 2. In example experiments 3 and 4, the SamplePopulation was modified to include spectra of both the Normal Populationand spectra of an additional population of 55 ICU patients. Thesespectra will be referred to as the “Normal+Target Spectra.” Inexperiments 3 and 4, the ICU patients included Surgical ICU patients,Medical ICU patients as well as victims of severe trauma, including alarge proportion of patients who had suffered major blood loss. Majorblood loss may necessitate replacement of the patient's total bloodvolume multiple times during a single day and subsequent treatment ofthe patient via electrolyte and/or fluid replacement therapies. Majorblood loss may also require administration of plasma-expandingmedications. Major blood loss may lead to significant deviations fromthe blood plasma spectra representative of a Normal Population. Thepopulation of 55 ICU patients (who provided the Target Spectra) has somesimilarities to the individuals for whom the analyses in experiments 1-4were performed (e.g., all were ICU patients), but in these experiments,target spectra from individuals in the target population were notincluded in the Target Spectra.

Results of example experiments 1-4 are shown in the following table. Theglucose concentrations estimated from the analysis method were comparedto independently determined glucose measurements to provide an averageprediction error and a standard deviation of the average predictionerror. The table demonstrates that independent of the Sample Populationused (e.g., either the Normal Population or the Normal+TargetPopulation), calibrating for interferents reduces both the averageprediction error and the standard deviation (e.g., compare the resultsfor experiment 2 to the results for experiment 1 and compare the resultsfor experiment 4 to the results for experiment 3). The table furtherdemonstrates that independent of the analysis method used (e.g., eitherPLS or PFIR), using a Sample Population with more similarity to thetarget population (e.g., the Normal+Target Population) reduces both theaverage prediction error and the standard deviation (e.g., compare theresults for experiment 3 to the results for experiment 1 and compare theresults for experiment 4 to the results for experiment 2).

Average Example Prediction Standard Experiment Interferent Sample ErrorDeviation No. Calibration Population (mg/dL) (mg/dL) 1 NO Normal 126 1642 YES Normal −6.8 23.2 3 NO Normal + Target 8.2 16.9 4 YES Normal +Target 1.32 12.6

Accordingly, embodiments of analysis methods that use a SamplePopulation that includes both normal spectra and spectra fromindividuals similar to those of the target population and that calibratefor possible interferents provide a good match between the estimatedglucose concentration and the measured glucose concentration. Asdiscussed above, a suitable Sample Population may be assembled from thePopulation Database in order to include normal spectra plus suitabletarget spectra from individuals that match a desired target populationincluding, for example, ICU patients, trauma patients, a particulardemographic group, a group having a common medical condition (e.g.,diabetes), and so forth.

User Interface

The system 400 can include a display system 414, for example, asdepicted in FIG. 4. The display system 414 may comprise an input deviceincluding, for example, a keypad or a keyboard, a mouse, a touchscreendisplay, and/or any other suitable device for inputting commands and/orinformation. The display system 414 may also include an output deviceincluding, for example, an LCD monitor, a CRT monitor, a touchscreendisplay, a printer, and/or any other suitable device for outputtingtext, graphics, images, videos, etc. In some embodiments, a touchscreendisplay is advantageously used for both input and output.

The display system 414 can include a user interface 2400 by which userscan conveniently and efficiently interact with the system 400. The userinterface 2400 may be displayed on the output device of the system 400(e.g., the touchscreen display). In some embodiments, the user interface2400 is implemented and/or stored as one or more code modules, which maybe embodied in hardware, firmware, and/or software.

FIGS. 24 and 25 schematically illustrate the visual appearance ofembodiments of the user interface 2400. The user interface 2400 may showpatient identification information 2402, which can include patient nameand/or a patient ID number. The user interface 2400 also can include thecurrent date and time 2404. An operating graphic 2406 shows theoperating status of the system 400. For example, as shown in FIGS. 24and 25, the operating status is “Running,” which indicates that thesystem 400 is fluidly connected to the patient (“Jill Doe”) andperforming normal system functions such as infusing fluid and/or drawingblood. The user interface 2400 can include one or more analyteconcentration graphics 2408, 2412, which may show the name of theanalyte and its last measured concentration. For example, the graphic2408 in FIG. 24 shows “Glucose” concentration of 150 mg/dL, while thegraphic 2412 shows “Lactate” concentration of 0.5 mmol/L. The particularanalytes displayed and their measurement units (e.g., mg/dL, mmol/L, orother suitable unit) may be selected by the user. The size of thegraphics 2408, 2412 may be selected to be easily readable out to adistance such as, e.g., 30 feet. The user interface 2400 may alsoinclude a next-reading graphic 2410 that indicates the time until thenext analyte measurement is to be taken. In FIG. 24, the time until nextreading is 3 minutes, whereas in FIG. 25, the time is 6 minutes, 13seconds.

The user interface 2400 can include an analyte concentration statusgraphic 2414 that indicates status of the patient's current analyteconcentration compared with a reference standard. For example, theanalyte may be glucose, and the reference standard may be a hospitalICU's tight glycemic control (TGC). In FIG. 24, the status graphic 2414displays “High Glucose,” because the glucose concentration (150 mg/dL)exceeds the maximum value of the reference standard. In FIG. 25, thestatus graphic 2414 displays “Low Glucose,” because the current glucoseconcentration (79 mg/dL) is below the minimum reference standard. If theanalyte concentration is within bounds of the reference standard, thestatus graphic 2414 may indicate normal (e.g., “Normal Glucose”), or itmay not be displayed at all. The status graphic 2414 may have abackground color (e.g., red) when the analyte concentration exceeds theacceptable bounds of the reference standard.

The user interface 2400 can include one or more trend indicators 2416that provide a graphic indicating the time history of the concentrationof an analyte of interest. In FIGS. 24 and 25, the trend indicator 2416comprises a graph of the glucose concentration (in mg/dL) versus elapsedtime (in hours) since the measurements started. The graph includes atrend line 2418 indicating the time-dependent glucose concentration. Inother embodiments, the trend line 2418 can include measurement errorbars and may be displayed as a series of individual data points. In FIG.25, the glucose trend indicator 2416 is shown as well as a trendindicator 2430 and trend line 2432 for the lactate concentration. Insome embodiments, a user may select whether none, one, or both trendindicators 2416, 2418 are displayed. In some embodiments, one or both ofthe trend indicators 2416, 2418 may appear only when the correspondinganalyte is in a range of interest such as, for example, above or belowthe bounds of a reference standard.

The user interface 2400 can include one or more buttons 2420-2426 thatcan be actuated by a user to provide additional functionality or tobring up suitable context-sensitive menus and/or screens. For example,in the embodiments shown in FIG. 24 and FIG. 25, four buttons 2420-2426are shown, although fewer or more buttons are used in other embodiments.The button 2420 (“End Monitoring”) may be pressed when one or moreremovable portions (see, e.g., 710 of FIG. 7) are to be removed. In manyembodiments, because the removable portions 710, 712 are not reusable, aconfirmation window appears when the button 2420 is pressed. If the useris certain that monitoring should stop, the user can confirm this byactuating an affirmative button in the confirmation window. If thebutton 2420 were pushed by mistake, the user can select a negativebutton in the confirmation window. If “End Monitoring” is confirmed, thesystem 400 performs appropriate actions to cease fluid infusion andblood draw and to permit ejection of a removable portion (e.g., theremovable portion 710).

The button 2422 (“Pause”) may be actuated by the user if patientmonitoring is to be interrupted but is not intended to end. For example,the “Pause” button 2422 may be actuated if the patient is to betemporarily disconnected from the system 400 (e.g., by disconnecting thetubes 306). After the patient is reconnected, the button 2422 may bepressed again to resume monitoring. In some embodiments, after the“Pause” button 2422 has been pressed, the button 2422 displays “Resume.”

The button 2424 (“Delay 5 Minutes”) causes the system 400 to delay thenext measurement by a delay time period (e.g., 5 minutes in the depictedembodiments). Actuating the delay button 2424 may be advantageous iftaking a reading would be temporarily inconvenient, for example, becausea health care professional is attending to other needs of the patient.The delay button 2424 may be pressed repeatedly to provide longerdelays. In some embodiments, pressing the delay button 2424 isineffective if the accumulated delay exceeds a maximum threshold. Thenext-reading graphic 2410 automatically increases the displayed timeuntil the next reading for every actuation of the delay button 2424 (upto the maximum delay).

The button 2426 (“Dose History”) may be actuated to bring up a dosinghistory window that displays patient dosing history for an analyte ormedicament of interest. For example, in some embodiments, the dosinghistory window displays insulin dosing history of the patient and/orappropriate hospital dosing protocols. A nurse attending the patient canactuate the dosing history button 2426 to determine the time when thepatient last received an insulin dose, the last dosage amount, and/orthe time and amount of the next dosage. The system 400 may receive thepatient dosing history via wired or wireless communications from ahospital information system.

In other embodiments, the user interface 2400 can include additionaland/or different buttons, menus, screens, graphics, etc. that are usedto implement additional and/or different functionalities.

Related Components

FIG. 26 schematically depicts various components and/or aspects of apatient monitoring system 2630 and how those components and/or aspectsrelate to each other. In some embodiments, the monitoring system 2630can be the apparatus 100 for withdrawing and analyzing fluid samples.Some of the depicted components can be included in a kit containing aplurality of components. Some of the depicted components, including, forexample, the components represented within the dashed rounded rectangle2640 of FIG. 26, are optional and/or can be sold separately from othercomponents.

The patient monitoring system 2630 shown in FIG. 26 includes amonitoring apparatus 2632. The monitoring apparatus 2632 can be themonitoring device 102, shown in FIG. 1 and/or the system 400 of FIG. 4.The monitoring apparatus 2632 can provide monitoring of physiologicalparameters of a patient. In some embodiments, the monitoring apparatus2632 measures glucose and/or lactate concentrations in the patient'sblood. In some embodiments, the measurement of such physiologicalparameters is substantially continuous. The monitoring apparatus 2632may also measure other physiological parameters of the patient. In someembodiments, the monitoring apparatus 2632 is used in an intensive careunit (ICU) environment. In some embodiments, one monitoring apparatus2632 is allocated to each patient room in an ICU.

The patient monitoring system 2630 can include an optional interfacecable 2642. In some embodiments, the interface cable 2642 connects themonitoring apparatus 2632 to a patient monitor (not shown). Theinterface cable 2642 can be used to transfer data from the monitoringapparatus 2632 to the patient monitor for display. In some embodiments,the patient monitor is a bedside cardiac monitor having a display thatis located in the patient room (see, e.g., the user interface 2400 shownin FIG. 24 and FIG. 25.) In some embodiments, the interface cable 2642transfers data from the monitoring apparatus 2632 to a central stationmonitor and/or to a hospital information system (HIS). The ability totransfer data to a central station monitor and/or to a HIS may depend onthe capabilities of the patient monitor system.

In the embodiment shown in FIG. 26, an optional bar code scanner 2644 isconnected to the monitoring apparatus 2632. In some embodiments, the barcode scanner 2644 is used to enter patient identification codes, nurseidentification codes, and/or other identifiers into the monitoringapparatus 2632. In some embodiments, the bar code scanner 2644 containsno moving parts. The bar code scanner 2644 can be operated by manuallysweeping the scanner 2644 across a printed bar code or by any othersuitable means. In some embodiments, the bar code scanner 2644 includesan elongated housing in the shape of a wand.

The patient monitoring system 2630 includes a fluid system kit 2634connected to the monitoring apparatus 2632. In some embodiments, thefluid system kit 2634 includes fluidic tubes that connect a fluid sourceto an analytic subsystem. For example, the fluidic tubes can facilitatefluid communication between a blood source or a saline source and anassembly including a sample holder and/or a centrifuge. In someembodiments, the fluid system kit 2634 includes many of the componentsthat enable operation of the monitoring apparatus 2632. In someembodiments, the fluid system kit 2634 can be used with anti-clottingagents (such as heparin), saline, a saline infusion set, a patientcatheter, a port sharing IV infusion pump, and/or an infusion set for anIV infusion pump, any or all of which may be made by a variety ofmanufacturers. In some embodiments, the fluid system kit 2634 includes amonolithic housing that is sterile and disposable. In some embodiments,at least a portion of the fluid system kit 2634 is designed for singlepatient use. For example, the fluid system kit 2634 can be constructedsuch that it can be economically discarded and replaced with a new fluidsystem kit 2634 for every new patient to which the patient monitoringsystem 2630 is connected. In addition, at least a portion of the fluidsystem kit 2634 can be designed to be discarded after a certain periodof use, such as a day, several days, several hours, three days, acombination of hours and days such as, for example, three days and twohours, or some other period of time. Limiting the period of use of thefluid system kit 2634 may decrease the risk of malfunction, infection,or other conditions that can result from use of a medical apparatus foran extended period of time.

In some embodiments, the fluid system kit 2634 includes a connector witha luer fitting for connection to a saline source. The connector may be,for example, a three-inch pigtail connector. In some embodiments, thefluid system kit 2634 can be used with a variety of spikes and/or IVsets used to connect to a saline bag. In some embodiments, the fluidsystem kit 2634 also includes a three-inch pigtail connector with a luerfitting for connection to one or more IV pumps. In some embodiments, thefluid system kit 2634 can be used with one or more IV sets made by avariety of manufacturers, including IV sets obtained by a user of thefluid system kit 2634 for use with an infusion pump. In someembodiments, the fluid system kit 2634 includes a tube with a low deadvolume luer connector for attachment to a patient vascular access point.For example, the tube can be approximately seven feet in length and canbe configured to connect to a proximal port of a cardiovascularcatheter. In some embodiments, the fluid system kit 2634 can be usedwith a variety of cardiovascular catheters, which can be supplied, forexample, by a user of the fluid system kit 2634.

As shown in FIG. 26, the monitoring apparatus 2632 is connected to asupport apparatus 2636, such as an IV pole. The support apparatus 2636can be customized for use with the monitoring apparatus 2632. A vendorof the monitoring apparatus 2632 may choose to bundle the monitoringapparatus 2632 with a custom support apparatus 2636. In someembodiments, the support apparatus 2636 includes a mounting platform forthe monitoring apparatus 2632. The mounting platform can include mountsthat are adapted to engage threaded inserts in the monitoring apparatus2632. The support apparatus 2636 can also include one or morecylindrical sections having a diameter of a standard IV pole, forexample, so that other medical devices, such as IV pumps, can be mountedto the support apparatus. The support apparatus 2636 can also include aclamp adapted to secure the apparatus to a hospital bed, an ICU bed, oranother variety of patient conveyance device.

In the embodiment shown in FIG. 26, the monitoring apparatus 2632 iselectrically connected to an optional computer system 2646. The computersystem 2646 can comprise one or multiple computers, and it can be usedto communicate with one or more monitoring devices. In an ICUenvironment, the computer system 2646 can be connected to at least someof the monitoring devices in the ICU. The computer system 2646 can beused to control configurations and settings for multiple monitoringdevices (for example, the system can be used to keep configurations andsettings of a group of monitoring devices common). The computer system2646 can also run optional software, such as data analysis software2648, HIS interface software 2650, and insulin dosing software 2652.

In some embodiments, the computer system 2646 runs optional dataanalysis software 2648 that organizes and presents information obtainedfrom one or more monitoring devices. In some embodiments, the dataanalysis software 2648 collects and analyzes data from the monitoringdevices in an ICU. The data analysis software 2648 can also presentcharts, graphs, and statistics to a user of the computer system 2646.

In some embodiments, the computer system 2646 runs optional hospitalinformation system (HIS) interface software 2650 that provides aninterface point between one or more monitoring devices and an HIS. TheHIS interface software 2650 may also be capable of communicating databetween one or more monitoring devices and a laboratory informationsystem (LIS).

In some embodiments, the computer system 2646 runs optional insulindosing software 2652 that provides a platform for implementation of aninsulin dosing regimen. In some embodiments, the hospital tight glycemiccontrol protocol is included in the software. The protocol allowscomputation of proper insulin doses for a patient connected to amonitoring device 2646. The insulin dosing software 2652 can communicatewith the monitoring device 2646 to ensure that proper insulin doses arecalculated.

Analyte Control and Monitoring

In some embodiments, it may be advantageous to control a level of ananalyte (e.g., glucose) in a patient using an embodiment of an analytedetection system described herein. Although certain examples of glucosecontrol are described below, embodiments of the systems and methodsdisclosed herein may be used to monitor and/or control other analytes(e.g., lactate).

For example, diabetic individuals control their glucose levels byadministration of insulin. If a diabetic patient is admitted to ahospital or ICU, the patient may be in a condition in which he or shecannot self-administer insulin. Advantageously, embodiments of theanalyte detection systems disclosed herein may be used to control thelevel of glucose in the patient. Additionally, it has been found that amajority of patients admitted to the ICU exhibit hyperglycemia withouthaving diabetes. In such patients it may be beneficial to monitor andcontrol their blood glucose level to be within a particular range ofvalues. Further, it has been shown that tightly controlling bloodglucose levels to be within a stringent range may be beneficial topatients undergoing surgical procedures.

A patient admitted to the ICU or undergoing surgery may be administereda variety of drugs and fluids such as Hetastarch, intravenousantibiotics, intravenous glucose, intravenous insulin, intravenousfluids such as saline, etc., which may act as interferents and make itdifficult to determine the blood glucose level. Moreover, the presenceof additional drugs and fluids in the blood stream may require differentmethods for measuring and controlling blood glucose level. Also, thepatient may exhibit significant changes in hematocrit levels due toblood loss or internal hemorrhage, and there can be unexpected changesin the blood gas level or a rise in the level of bilirubin and ammonialevels in the event of an organ failure. Embodiments of the systems andmethods disclosed herein advantageously may be used to monitor andcontrol blood glucose (and/or other analytes) in the presence ofpossible interferents to estimation of glucose and for patientsexperiencing health problems.

In some environments, Tight Glycemic Control (TGC) can include: (1)substantially continuous monitoring (which can include periodicmonitoring, at relatively frequent intervals of every 1, 5, 15, 30, 45,and/or 60 minutes, for example) of glucose levels; (2) determination ofsubstances that tend to increase glucose levels (e.g., sugars such asdextrose) and/or decrease glucose levels (e.g., insulin); and/or (3)responsive delivery of one or more of such substances, if appropriateunder the controlling TGC protocol. For example, one possible TGCprotocol can be achieved by controlling glucose within a relativelynarrow range (for example between 70 mg/dL to 110 mg/dL). As will befurther described, in some embodiments, TGC may be achieved by using ananalyte monitoring system to make continuous and/or periodic butfrequent measurements of glucose levels.

In some embodiments, the analyte detection system schematicallyillustrated in FIGS. 4, 5, and 6 may be used to regulate theconcentration of one or more analytes in the sample in addition todetermining and monitoring the concentration of the one or moreanalytes. In some cases, the analyte detection system may be used in anICU to monitor (and/or control) analytes that may be present in patientsexperiencing trauma. In some implementations, the concentration of theanalytes is regulated to be within a certain range. The range may bepredetermined (e.g., according to a hospital protocol or a physician'srecommendation), or the range may be adjusted as conditions change.

In an example of glycemic control, a system can be used to determine andmonitor the concentration of glucose in the sample. If the concentrationof glucose falls below a lower threshold, glucose from an externalsource can be supplied. If the concentration of glucose increases abovean upper threshold, insulin from an external source can be supplied. Insome embodiments, glucose or insulin may be infused in a patientcontinuously over a certain time interval or may be injected in a largequantity at once (referred to as “bolus injection”).

In some embodiments, a glycemic control system may be capable ofdelivering glucose, dextrose, glycogen, and/or glucagon from an externalsource relatively quickly in the event of hypoglycemia. As discussed,embodiments of the glycemic control system may be capable of deliveringinsulin from an external source relatively quickly in the event ofhyperglycemia.

Returning to FIGS. 5 and 6, these figures schematically illustrateembodiments of a fluid handling system that comprise optional analytecontrol subsystems 2780. The analyte control subsystem 2780 may be usedfor providing control of an analyte such as, e.g., glucose, and mayprovide delivery of the analyte and/or related substances (e.g.,dextrose solution and/or insulin in the case of glucose). The analytecontrol subsystem 2780 comprises a source 2782 such as, for example, theanalyte (or a suitable compound related to the analyte) dissolved inwater or saline. For example, if the analyte is glucose, the source 2782may comprise a bag of dextrose solution (e.g., Dextrose or Dextrose50%). The source 2782 can be coupled to an infusion pump (not shown).The source 2782 and the infusion pump can be provided separately fromthe analyte control subsystem 2780. For example, a hospitaladvantageously can use existing dextrose bags and infusion pumps withthe subsystem 2780.

As schematically illustrated in FIGS. 5 and 6, the source 2782 is influid communication with the patient tube 512 via a tube 2784 andsuitable connectors. A pinch valve 2786 may be disposed adjacent thetube 2784 to regulate the flow of fluid from the source 2782. A patientinjection port can be located at a short distance from the proximal portof the central venous catheter or some other catheter connected to thepatient.

In an example implementation for glycemic control, if the analytedetection system determines that the level of glucose has fallen below alower threshold value (e.g., the patient is hypoglycemic), a controlsystem (e.g., the fluid system controller 405 in some embodiments)controlling an infusion delivery system may close the pinch valves 521and/or 542 to prevent infusion of insulin and/or saline into thepatient. The control system may open the pinch valve 2786 and dextrosesolution from the source 2782 can be infused (or alternatively injectedas a bolus) into the patient. After a suitable amount of dextrosesolution has been infused to the patient, the pinch valve 2786 can beclosed, and the pinch valves 521 and/or 542 can be opened to allow flowof insulin and/or saline. In some systems, the amount of dextrosesolution for infusion (or bolus injection) may be calculated based onone or more detected concentration levels of glucose. The source 2782advantageously may be located at a short enough fluidic distance fromthe patient such that dextrose can be delivered to the patient within atime period of about one to about ten minutes. In other embodiments, thesource 2782 can be located at the site where the patient tube 512interfaces with the patient so that dextrose can be delivered withinabout one minute.

If the analyte detection system determines that the level of glucose hasincreased above an upper threshold value (e.g., the patient ishyperglycemic), the control system may close the pinch valves 542 and/or2786 to prevent infusion of saline and/or dextrose into the patient. Thecontrol system may open the pinch valve 521, and insulin can be infused(or alternatively injected as a bolus) into the patient. After asuitable amount of insulin has been infused (or bolus injected) to thepatient, the control system can close the pinch valve 521 and open thepinch valves 542 and/or 2786 to allow flow of saline and/or glucose. Thesuitable amount of insulin may be calculated based on one or moredetected concentration levels of glucose in the patient. The insulinsource 518 advantageously may be located at a short enough fluidicdistance from the patient such that insulin can be delivered to thepatient within about one to about ten minutes. In other embodiments, theinsulin source 518 may be located at the site where the patient tube 512interfaces with the patient so that insulin can be delivered to thepatient within about one minute.

In some embodiments, sampling bodily fluid from a patient and providingmedication to the patient may be achieved through the same lines of thefluid handling system. For example, in some embodiments, a port to apatient can be shared by alternately drawing samples and medicatingthrough the same line. In some embodiments, a bolus can be provided tothe patient at regular intervals (in the same or different lines). Forexample, a bolus of insulin can be provided to a patient after meals. Inanother embodiment comprising a shared line, a bolus of medication canbe delivered when returning part of a body fluid sample back to thepatient. In some implementations, the bolus of medication is deliveredmidway between samples (e.g., every 7.5 minutes if samples are drawnevery 15 minutes). In other embodiment, a dual lumen tube can be used,wherein one lumen is used for the sample and the other lumen tomedicate. In yet another embodiment, an analyte detection system (e.g.,an OPTISCANNER™ monitor) may provide suitable commands to a separateinsulin pump (on a shared port or different line).

Example Method for Glycemic Control

FIG. 27 is a flowchart that schematically illustrates an exampleembodiment of a method 2700 of providing analyte control. The exampleembodiment is directed toward one possible implementation for glycemiccontrol (including but not limited to tight glycemic control) and isintended to illustrate certain aspects of the method 2700 and is notintended to limit the scope of possible analyte control methods. Inblock 2705, a glucose monitoring apparatus (e.g., the monitoringapparatus 2632 of FIG. 26) draws a sample (e.g., a blood or blood plasmasample) from a sample source (e.g., a patient) and obtains a measurementfrom the sample (e.g., a portion of the drawn sample). The measurementmay comprise an optical measurement such as, for example, an infraredspectrum of the sample. In block 2710, the measurement sample isanalyzed to identify possible interferents to an estimation of theglucose concentration in the measurement sample. In block 2715, a modelis generated for estimating the glucose concentration from the obtainedmeasurement. In some embodiments, models developed from the algorithmsdescribe above with reference to FIGS. 21-23 are used. The generatedmodel may reduce or minimize effects of the identified interferents onthe estimated glucose concentration, in certain embodiments. In block2720, an estimated glucose concentration is determined from the modeland the obtained measurement. In block 2725, the estimated glucoseconcentration in the sample is compared to an acceptable range ofconcentrations. The acceptable range may be determined according to asuitable glycemic control protocol such as, for example, a TGC protocol.For example, in certain TGC protocols the acceptable range may be aglucose concentration in a range from about 70 mg/dL to about 110 mg/dL.If the estimated glucose concentration lies within the acceptable range,the method 2700 returns to block 2705 to obtain the next samplemeasurement, which may be made within about one to about thirty minutes(e.g., every fifteen minutes).

In block 2725, if the estimated glucose concentration is outside theacceptable range of concentrations, then the method 2700 proceeds toblock 2740 in which the estimated glucose concentration is compared witha desired glucose concentration. The desired glucose concentration maybe based on, for example, the acceptable range of glucoseconcentrations, the parameters of the particular glycemic protocol, thepatient's estimated glucose concentration, and so forth. If theestimated glucose concentration is below the desired concentration(e.g., the patient is hypoglycemic), a dose of dextrose to be deliveredto the patient is calculated in block 2745. This calculation may takeinto account various factors including, for example, one or moreestimated glucose concentrations, presence of additional drugs in thepatient's system, time taken for dextrose to be assimilated by thepatient, and the delivery method (e.g., continuous infusion or bolusinjection). In block 2750, a fluid delivery system (e.g., a system suchas the optional subsystem 2780 shown in FIGS. 5 and 6) delivers thecalculated dose of dextrose to the patient.

In block 2740, if the estimated glucose concentration is greater thanthe desired concentration (e.g., the patient is hyperglycemic), a doseof insulin to be delivered is calculated in block 2755. The dose ofinsulin may depend on various factors including, for example, one ormore estimated glucose concentrations in the patient, presence of otherdrugs, type of insulin used, time taken for insulin to be assimilated bythe patient, method of delivery (e.g., continuous infusion or bolusinjection), etc. In block 2750, a fluid delivery system (e.g., theoptional subsystem 2780 shown in FIGS. 5 and 6) delivers the calculateddose of insulin to the patient.

In block 2765, the method 2700 returns to block 2705 to await the startof the next measurement cycle, which may be within about one to aboutthirty minutes (e.g., every fifteen minutes). In some embodiments, thenext measurement cycle begins at a different time than normallyscheduled in cases in which the estimated glucose concentration liesoutside the acceptable range of concentrations under the glycemicprotocol. Such embodiments advantageously allow the system to monitorresponse of the patient to the delivered dose of dextrose (or insulin).In some such embodiments, the time between measurement cycles is reducedso the system can more accurately monitor analyte levels in the patient.

Examples of Some Possible Additional or Alternative Analytes

Although examples of control and/or monitoring has been described in theillustrative context of glycemic control, embodiments of the systems andmethods can be configured for control and/or monitoring of one or moreof many possible analytes, in addition to or instead of glucose. Monitorand/or control of analytes may be particularly helpful in ICUs, whichreceive patients experiencing trauma. For example, another parameterthat can be monitored is level of Hemoglobin (Hb). If the Hb level of apatient goes down without an apparent external reason, the patient couldbe suffering from internal bleeding. Indeed, many ICU patients (someestimate as many as 10%) suffer from what appears to be spontaneousinternal bleeding that may not be otherwise detectable until theconsequences are too drastic to easily overcome. In some embodiments,level of Hb can be measured indirectly, because its relationship tooxygen in the veins and arteries (at different points in the vasculaturewith respect to the heart and lungs) is understood. In some embodiments,the apparatus, systems and methods described herein can be useful formeasuring a level of Hb.

Another parameter that can be monitored is lactate level, which can berelated to sepsis or toxic shock. Indeed, high levels and/or rapid risein lactate levels can be correlated to organ failure and oxygenationproblems in the blood and organs. However, other direct measures of thebiological effects related to lactate level problems can be difficult tomeasure, for example, only becoming measurable with a delay (e.g., 2-6hours later). Thus, measurement of lactate level can help provide avaluable early warning of other medical problems. Indeed, if a problemwith lactate levels is detected, a nurse or doctor may be able toprevent the correlated problems by providing more fluids.

Another parameter that can be monitored is central venous oxygensaturation (ScvO2). It can be advantageous to try to maintain a ScvO2 of65-70% or greater in ICU patients (to help avoid sepsis, for example).In some embodiments, the apparatus, systems, and methods describedherein can be useful for measuring a level of ScvO2.

Levels of lactate and ScvO2 in a patient can be used together to provideinformation and/or warnings to a health care provider, which can beespecially useful in an ICU setting. For example, if lactate and ScvO2are both high, a warning can be provided (e.g., automatically using analarm). If lactate is high, but ScvO2 is low, a patient may benefit fromadditional fluids. If ScvO2 is high, but lactate is low, a cardiacproblem may be indicated. Thus, a system that provides information aboutboth lactate and ScvO2 can be very beneficial to a patient, especially,for example, in the ICU environment. Although lactate and ScvO2 havebeen used as an illustrative example, in other embodiments differentcombinations of analytes may be monitored and used to provideinformation and/or warnings to a health care provider.

An analyte monitoring apparatus can be usefully configured to draw bloodfrom the body and analyze a portion of that blood. One useful assumptionto make is that the drawn and analyzed blood is representative of theother blood that remains in the body and is not analyzed. This can be avalid assumption in many cases because blood flow in the body is aturbulent process, with the heart urging the blood through vessels andorgans and tissue having various diameters and various levels of flowresistance. Indeed, there can be a great amount of variation in the flowrate of blood as it passes through the many regions of the body. Thisturbulence and variation of flow rates will, tend to mix blood withinthe body, which will prevent blood in one part of the body from having asubstantially different composition than blood in other parts of thebody.

An analyte monitoring apparatus can also be usefully configured to beinserted into the body, and, for example, into the blood stream. Thiscan have the advantage of eliminating any need to transport the bloodout of the body; it can also introduce other potential risks. However,even if a monitoring device is inserted into the body, at any given timethe device is likely only capable of measuring an analyte in a limitedportion of the blood—for example, the blood that is in contact with (orwithin the view of) a sensor in the device. Thus, even in this case itis useful to assume that this limited portion of the blood isrepresentative of the other blood in the body.

Some systems do not measure over a fixed amount of blood, but insteadassume a constant relationship between the analyte in local blood andthe amount of blood overall in the body. Such a constant relationshipcan be referred to as a stoichiometric relationship. If this assumptionis inaccurate, results of the analysis can be inaccurate. This potentialproblem can be amplified when measurements are taken, for example, in aportion of the blood flow that has a varying rate of the analyte (e.g.,for physiological reasons). For example, measurement of oxygen in theblood inside the lungs can be difficult over time because the lungsintroduce blood into the oxygen periodically but at relatively shortintervals. An indwelling system that is constantly measuring the glucoselevel of the blood that flows by and/or through its sensors may providea reading that is too local and not provide a consistently usefuloverview of the amount of analyte generally present in the body as awhole. One way to avoid inaccuracies due to failures of this assumptionis to measure an amount of analyte in a fixed amount of blood, drawnfrom a portion of the bloodstream that is physiologically likely tomaintain a relatively constant level of the analyte in question. In manycases, the larger the blood sample, the less likely it will be toreflect misleading and/or temporary local distortions in an analytelevel. Accordingly, ex-vivo systems that withdraw blood can have someadvantages over systems with sensors that are inserted into the bodynotwithstanding the potential difficulties of repeatedly withdrawingblood out of the body and reducing clot risk in ex-vivo fluid systems.

Patient Connector Configured to Reduce Flow Separation

In systems and devices including fluid flow through a tube or a channel,the fluid can flow at different speeds and have different flow patternsat different positions across the width of the tube. For example, thelayer of fluid flowing close to the inner walls of the tube or channel,also referred to as the boundary layer, can exhibit either laminar flowor turbulent flow. In various embodiments, when the boundary layertravels far enough against an opposing pressure gradient, the speed ofthe boundary layer can fall almost to zero. The fluid flow can becomedetached from the surface of the object and can form eddies andvortices. Flow separation can also occur in systems and devicesincluding fluid flow across a junction (e.g. at a junction of two tubesor fluid channels having different internal diameters, or at a junctionacross two connectors). The speed of the flow will generally transitionsmoothly from a first speed to a second speed if the junction has asubstantially smooth transition. In systems where the speed of the flowtransitions smoothly from a first speed to a second speed across ajunction, the flow can be generally along the internal walls of theconnectors and tubes included in the junction. However, if the junctionhas an abrupt or a substantially unsmooth transition, then the fluidflow can also exhibit an abrupt or a substantially unsmooth transitionfrom a first speed to a second speed. In systems where the speed of theflow transitions abruptly or substantially not smoothly from a firstspeed to a second speed across a junction, the flow can be disrupted andneed not generally be along the internal walls of the connectors andtubes included in the junction. In various embodiments of the analytemonitoring system described herein, it is advantageous to prevent orsubstantially reduce separated fluid flow within various tubes andchannels and across the various fluidic junctions. As discussed above,when fluid flow in the fluidic channels and tubes or across variousfluidic junctions separates, the speed of the fluid within the boundarylayer can fall almost to zero and the fluid flow can stagnate. Thisstagnation of the fluid flow can result in accumulation of the fluidalong the walls of the fluidic channels and tubes and/or at the variousfluidic junctions. Accumulation of fluid can result in clogging of thefluidic channels and/or tubes and fluidic junctions especially when thefluid comprises a bodily fluid such as blood that can coagulate. Thus,in various embodiments, preventing or reducing separated flow across thevarious fluidic junctions during withdrawing the sample from the patientand returning the unused sample back to the patient can substantiallyincrease the time over which the tubes and connectors in the analytemonitoring system can be used, since the tubes and connectors may notclog as frequently when separated flow is prevented or substantiallyreduced. For example, in various embodiments prevent the tubes and theconnectors connecting the analyte monitoring system to the patient canbe used for several days before they have to be changed and/or cleanedif separated flow is prevented or substantially reduced within thevarious tubes and channels and across the various fluidic junctions whenwithdrawing or returning a sample from or to the patient.

Various embodiments of the patient connector configured to prevent orsubstantially reduce separated flow can allow connection of the analytemonitoring system to different types of patient catheters, for example,central venous catheter (CVC), peripherally inserted central catheter(PICC), and/or peripheral IV catheters. Various embodiments of thepatient connector described herein can also connect to other embodimentscatheters not disclosed above. CVCs can be generally used when asubstantially large amount of fluid is required and the vascular accessis compromised or unavailable. For example, vascular access can becompromised if peripheral veins are either unavailable or not availablein sufficient quantity. In various embodiments, the CVC may includemultiple lumens (e.g. 2, 3 or 5). In various embodiments of the CVC, thediameter of the inlet can be approximately equal to the diameter of theoutlet. In some embodiments, the analyte monitoring system describedabove can connect to the proximal port of the CVC. In variousembodiments, the proximal port can be the port wherein the outlet of theinfusate is the closest to the caregiver or medical practitioner. Insome embodiments, the proximal port can be the port wherein the outletof the infusate is farthest from the inserted tip of the catheter. Invarious embodiments, an advantage of using the proximal port of the CVCis that no other medications or drugs are infused through this port.Another advantage of using the proximal CVC port is that because theflow rate in the central cavity of the heart where the catheter isplaced is substantially large, the downstream infusions (from the mid orthe distal port) do not substantially mix with the blood in the area ofthe proximal port. Thus the withdrawn blood can be substantiallyundiluted and have substantially less number of interfering compoundsthereby resulting in substantially accurate measurements. Generally,heath care practitioners can use the proximal port for drawing blood foranalysis, but they may clamp the other ports of the CVC (e.g. distal ormid ports) while blood is being drawn from the proximal port. Variousembodiments of the analyte monitoring system employ novel push/pullfluidics systems that allow the use of the proximal port of the CVCwhile other ports (e.g. mid or distal ports) are in use as well becausethe various embodiments of the analyte monitoring system describedherein can withdraw the sample at a slower rate than a health carepractitioner would.

PICCs can be threaded from the hand to the same chamber as the CVC. Invarious embodiments of the PICCs, the diameter of the inlet can beapproximately equal to the diameter of the outlet. Various embodimentsof the PICC lines can offer a lower risk for the patient in terms ofhospital acquired infection. In various embodiments, it's easier to keepPICC lines free of infection. In some embodiments, the location of thePICC lines can reduce the risk of infection to a patient. Variousembodiments of the PICC lines including single outlet or multipleoutlets can be used with the various embodiments of the analytemonitoring system described above. For example, in some embodiments ofthe analyte monitoring system (e.g. the OptiScan® device) a two channelmultiple outlet PICC can be used. The outlets of the two channelmultiple outlet PICC can be spaced apart. Various embodiments of theanalyte monitoring system described above can use a dedicated outletport of the PICC line with no other medications or drugs flowing in orout of the PICC line. An advantage of having a dedicated outlet port isa reduced risk of contamination or dilution of the sample therebysubstantially increasing the accuracy of the measurement. In variousembodiments, the analyte monitoring system described above can use asingle channel PICC having a single outlet that is dedicated to theanalyte monitoring system.

Peripheral IV catheters (Peripherals) are short catheters (e.g. having a1-2″ tip on a conical shaped body) that are inserted directly into theperipheral vein of an arm or hand of the patient. In various embodimentsof the analyte monitoring system including peripheral IV catheter, theperipheral IV catheter can be connected to the antecubital vein or themedian cubital vein. Various embodiments of the analyte monitoringincluding the peripheral IV catheters can be used in an Emergency Roomsetting, a clinical setting, or an intermediary care setting where acentral line access and/or professionals trained in the placement ofCVCs or PICCs are unavailable. Various embodiments of the analytemonitoring including the peripheral IV catheters can also be used in ICUsettings. Various embodiments of the analyte monitoring including theperipheral IV catheters can also be used to monitor and control theglucose and other analyte levels in patients who have undergone surgerysuch as Coronary Artery Bypass Grafting (CABG) surgery or some othersurgery, which may make placing a CVC line difficult.

Various embodiments of the peripheral IV catheters can be substantiallydifferent in shape as compared to the CVCs or PICCs. Thus, theperipheral IV catheters can have different flow dynamics as compared tothe CVCs or PICCs. For example, in some embodiments, the peripheral IVcatheters can have a tapering body which narrows down to a tip that isconstant and is substantially smaller in outer diameter than the largestcircumference of the body of the Various embodiments of the analytemonitoring including the peripheral IV catheters can also be used in ICUsettings. This shape of the peripheral IV catheters can cause abackpressure when a fluid is flushed through the peripheral IV catheter.The backpressure can cause a build up of the fluid along the inner wallsof the peripheral IV catheter which can result in clogging of thecatheter. The backpressure on the fluid is substantially reduced incatheters not having such a shape (e.g. a CVC or a PICC). As discussed,above a patient connector configured to prevent or substantially reduceseparated fluid flow when connected to the peripheral IV catheter canreduce the fluid buildup in the catheter and/or the connector and thusreduce the time over which the catheter and/or the connector will clog.

FIG. 28A shows a cross-sectional view of a male Luer hub connector 2800which conforms to the primary standards for dimensional and performancerequirements (e.g. ISO 594). The connector 2800 can be used to connectthe apparatus 100 of FIG. 1 to a patient 302 as shown in FIG. 28A. Asdiscussed above with reference to FIG. 1 and FIG. 3, the monitoringdevice 102 can be used to determine the concentration of one or moresubstances in a sample fluid. The sample fluid can come from the patient302, as illustrated in FIG. 28B. The male Luer hub connector may bemanufactured by a variety of manufacturers (e.g. C.R. Bard InternationalLtd., Cook Medical, etc.). FIG. 28B shows a cross-sectional view of astandard male Luer hub connector including an extension region 2801. Theextension region 2801 can reduce dead-space volume in the catheter. Theadvantages of including the extension region 2801 are discussed in U.S.patent application Ser. No. 12/122,009 filed on May 16, 2008 titled“LOW-VOLUME FITTINGS” (U.S. Publication No. 2008-0284167) which isincorporated by reference herein in its entirety. The shapes of variousembodiments of the extension region 2801 and the materials used to formthe extension regions are also discussed in detail in U.S. patentapplication Ser. No. 12/122,009 filed on May 16, 2008 titled “LOW-VOLUMEFITTINGS” (U.S. Publication No. 2008-0284167) which is incorporated byreference herein in its entirety. FIGS. 29A-29D illustrate variousembodiments of standard Luer connectors 2900, 2901, 2902 and 2903 (e.g.Bard, Cook and Arrow Luer connectors) conforming to ISO Luer standardsthat include an extension region 2901. The structure, materials andadvantages of the different Luer connectors including an extension arediscussed in detail in U.S. patent application Ser. No. 12/122,009 filedon May 16, 2008 titled “LOW-VOLUME FITTINGS” (U.S. Publication No.2008-0284167) which is incorporated by reference herein in its entirety.

FIGS. 30A and 30B illustrate embodiments of a patient connector 3000including a flow director configured to prevent or substantially reduceseparated flow. In various embodiments, the patient connector 3000 cancomprise a standard male Luer connector 3001 and a flow director 3002.In various embodiments, a spin lock ring may be provided to the standardmale connector which can partially overlap a standard female Luerconnector that mates with the standard male Luer connector 3001. Invarious embodiments, the spin lock ring can be threaded.

FIGS. 30C1-30C3 schematically illustrate different views for anembodiment of a patient connector similar to the embodiments shown inFIGS. 30A and 30B. FIG. 30C1 shows a perspective view of an embodimentof the patient connector. The patient connector shown in FIG. 30C1comprises three parts viz. a male Luer connector 3003, a flow director3004 and a spin lock ring 3005. In various embodiments, the male Luerconnector 3003 may conform to primary standards for dimensional andperformance requirements (e.g. ISO 594). The male Luer connector 3003 isconfigured to connect with a matching female Luer connector which canhave external threads. In various embodiments, the spin lock ring 3005can surround the male Luer connector 3003. The spin lock ring 3005 canhave internal threads 3006 that match with the external threads on thefemale Luer connector. The spin lock ring 3005 may facilitate a secureconnection between the male and the female Luer connectors. The maleLuer connector 3003 at its distal end is connected to the analytemonitoring system described herein. In various embodiments, the flowdirector 3004 is configured to fit into the male Luer connector 3003 asshown in FIG. 30C2 and FIG. 30C3. In various embodiments, the male Luerconnector 3003 and the flow director 3004 may be fabricated from a clearpolycarbonate material.

FIG. 30C2 shows the side-view of an assembled patient connector with theflow director 3004 fit into the male Luer connector 3003. As shown inFIG. 30C2, in various embodiments, the male Luer connector can include aflange 3006 and a Luer taper 3007. In various embodiments, the length ofthe Luer connector 3003 between the flange 3006 and the tip of the flowdirector 3007 can range from approximately 0.56 inches to approximately.0.58 inches. FIG. 30C3 shows a perspective view of the assembled patientconnector.

FIGS. 30D1-30D6 show different views of the male Luer connector 3003.FIG. 30D1 is a side view of the male Luer connector 3003 comprising aflange 3006, a Luer taper 3007 and a cylindrical region 3008. FIG. 30D2shows a view of the Luer connector 3003 through along the line A-A,while FIG. 30D3 shows the perspective of the Luer connector along theline A-A. As seen from FIGS. 30D2 and 30D3, the Luer connector 3003 hasa generally circular cross-section in the plane perpendicular to theline A-A. In various embodiments, the Luer connector 3003 may includetubing support spars 3008 as shown in FIGS. 30D2 and 30D3. In variousembodiments, the angular separation between two tubing support spars canbe approximately 120 degrees. FIG. 30D4 shows another view of the Luerconnector 3003 along the line A-A. FIG. 30D5 shows a cross-sectionalview of the Luer connector shown in FIG. 30D1 while FIG. 30D6 shows aperspective view of the Luer connector shown in FIG. 30D1.

FIGS. 30E1-30E4 shows different views of the flow director 3004. FIG.30E1 shows a perspective view of the flow director 3004. The flowdirector 3004 comprises an elongated region 3009 and a bulbous region3010. In various embodiments, the bulbous region 3010 can be spherical,frusto-conical, cylindrical or can be enlarged in shape. The bulbousregion 3010 can have other shapes as well. The elongated region 3009 isconfigured to fit in the interior of the male Luer connector 3003. Theelongated region 3009 can have a plurality of weld areas 3011 which areconfigured to contact the internal walls of the male Luer connector 3003and hold the flow director 3004 in place. The area between the weldareas 3011 which do not contact the internal walls of the male Luerconnector 3003 form grooves or channels through which the fluid canflow. In various embodiments, the flow director can have two, three,four or more weld areas.

FIGS. 30E2 and 30E3 show alternate views of the flow director 3004. FIG.30E4 shows a cross sectional view of the flow director 3004 through theline A-A of FIG. 30E2.

FIG. 31 shows an embodiment of a set-up that is used to attach (e.g. bywelding, by joining, by bonding, etc.) the flow director to the internalwalls of the Luer connector. The set-up includes an ultrasound device(e.g. an ultrasound horn) 3101 capable of providing ultrasound signalsor energy. The set-up further includes a holder 3102 configured tosupport the male Luer connector 3103 during the attaching process. Invarious embodiments, the ultrasound device 3101 can be configured tosupport the flow director 3104 during the attaching process.

During the attaching process, the ultrasound device provides ultrasoundenergy to the flow director 3102 which causes the weld areas (e.g. 3011of the flow director 3004) to heat and attach to the internal walls ofthe male Luer connector 3003. As discussed above, the area between theweld areas forms grooves or channels for allowing fluid flow.

FIGS. 32A-32E show fluid flow patterns through various embodiments of apatient connector. The information provided in FIGS. 32A-32E are flowstream lines that are color coded to indicate the magnitudes of thevelocity vector (e.g. speed). FIGS. 32A-1-32E-1 are color versions ofFIGS. 32A-32E which illustrate the flow stream lines in color. FIG. 32Ashows the flow of fluid through a patient connector that is attached tothe various embodiments of the analyte monitoring system describedabove. The direction of fluid flow is from right to left. As seen fromFIG. 32A, the fluid streamlines illustrate regions of substantiallynon-separated flow 3207 and 3209, wherein the fluid streamlines havemagnitude of the velocity vector between approximately 0.38 m/s (shownby the color code Green II) and approximately 0.19 m/s (shown by colorcode Blue II). FIG. 32A also shows areas of separated flow 3205 and3203, wherein the fluid streamlines have magnitude of the velocityvector between approximately 0.13 m/s (shown by color code Blue III) andapproximately 0 m/s (shown by color code Blue IV). In other embodiments,the magnitudes of the velocity vector for the fluid streamlines can bedifferent (e.g. higher or lower) from the values presented above.

FIG. 32B shows the flow of fluid through a patient connector thatincludes a standard female Luer connector and a male Luer connectorhaving a tapered internal region 3202. The direction of fluid flow isfrom right to left. The fluid flow is substantially less separated inthe embodiment shown in FIG. 32B as compared to the embodiment shown inFIG. 32A as can be observed from the fluid streamlines. As can be seenin FIG. 32B, the fluid streamlines illustrate regions of substantiallynon-separated flow 3211, 3213 and 3217, wherein the fluid streamlineshave magnitude of the velocity vector between approximately 0.38 m/s(shown by the color code Green II) and approximately 0.13 m/s (shown bycolor code Blue II). FIG. 32B also shows regions of slow flowing fluid3215, wherein the fluid streamlines have magnitude of the velocityvector between approximately 0.13 m/s (shown by color code Blue III) andapproximately 0 m/s (shown by color code Blue IV). In other embodiments,the magnitudes of the velocity vector for the fluid streamlines can bedifferent (e.g. higher or lower) from the values presented above.

FIGS. 32C-32E show the flow of fluid through a patient connector thatincludes a flow director as described above. The flow of fluid is fromright to left in FIGS. 32C and 32E and from left to right in FIG. 32D.As can be observed from FIG. 32C, the fluid flow streamlines showregions 3219, 3221 and 3225 where the magnitude of the velocity vectorof the fluid flow is between approximately 0.39 m/s (shown by color codeGreen II) and approximately 0.13 m/s (shown by color code Blue II). Theregions 3223 and 3227 shown in FIG. 32C show areas where the magnitudeof the velocity vector of the fluid flow streamline is betweenapproximately 0.13 m/s (shown by color code Blue III) and approximately0 m/s (shown by color code Blue IV).

FIG. 32D illustrates the fluid flow pattern in an embodiment of apatient connector including a flow director. These regions are depictedwith boundaries shown as solid lines, to aid in the illustration anddescription. However, each region is not actually distinct or physicallyseparated from any of the other regions. The general fluid velocitieschange within regions and across the illustrated boundaries in a smoothand non-abrupt manner. Moreover, each of these regions isthree-dimensional and, because each depicts fluid flow velocities in astructure having general cylindrical symmetry, the regions of commonflow velocities are generally cylindrically symmetrical. For ease ofillustration, the regions are depicted in cross-section, while the flowdirector is shaded to indicate three-dimensional contours. In the region3229 the magnitude of the velocity vector of the fluid flow streamlineis between approximately 0.13 m/s (shown by color code Red) andapproximately 0.11 m/s. In the region 3231 which is closer to the wallsof the patient connector near the tapered end of the flow director, themagnitude of the velocity vector of the fluid flow streamline is betweenapproximately 0.08 m/s (shown by color code Green I) and approximately0.05 m/s (shown by color code Green III). In the region 3233 between thelateral edges of the flow director and the wall of the patient connectorthe magnitude of the velocity vector of the fluid flow streamline isbetween approximately 0.11 m/s (shown by color code Yellow) andapproximately 0.08 m/s (shown by color code Green I). The fluid flow cansmoothly transition from region 3229 to region 3233 without any abruptchanges in the flow direction or flow velocity. As can be seen from FIG.32D, that the magnitude of the velocity vector of the fluid flowstreamline in the region 3239, near the bulbous portion of the flowdirector is between approximately 0.08 m/s (shown by the color codeGreen I) and 0.05 m/s (shown by the color code Green III) and themagnitude of the velocity vector of the fluid flow streamlines in theregions 3235 near the tip of the bulbous portion of the flow director isbetween approximately 0.02 m/s (shown by the color code Blue II) and 0m/s (shown by the color code Blue IV). The magnitude of the velocityvector of the fluid flow streamlines in areas 3241 and 3237 is betweenapproximately 0.04 m/s (shown by the color code Blue I) and 0 m/s (shownby the color code Blue IV).

FIG. 32E shows regions 3243, 3245 and 3249 where the magnitude of thevelocity vector of the fluid flow streamlines is between approximately0.38 m/s (shown by color code Green I) and approximately 0.13 m/s (shownby color code Blue II). The magnitude of the velocity vector of thefluid flow streamlines near the bulbous portion of the flow director isbetween approximately 0.13 m/s (shown by color code Blue III) andapproximately 0 m/s (shown by color code Blue IV).

FIG. 33A shows an embodiment of a patient connector 3300 comprising aflow director 3301. The patient connector has a patient end 3302 whichis proximal to the patient. In various embodiments, the patient end 3302can comprise a standard female Luer connector. The analyte end 3303which is farther from the patient end 3302 is connected to an analytemonitoring system. In various embodiments, the end 3303 can comprise amale Luer connector. In various embodiments, the flow director can beattached to the male Luer connector. FIG. 33B shows the flow of a fluidthrough the patient connector 3300 shown in FIG. 33A. FIG. 33C shows thepatient connector 3300 after use for an extended period of time. In someembodiments, the patient connector including a flow director can be usedwithout any significant accumulation for up to 6 hours. In variousembodiments, the patient connector including a flow director can be usedwithout any significant accumulation for up to 60 hours. It can be seenfrom FIG. 33C that there is some accumulation of fluid in the region3304.

FIG. 34A shows an experimental set-up 3400 to test the ability of thepatient connector including a flow director to prevent or substantiallyreduce separated flow. The set-up includes a source of bodily fluid(e.g. whole blood, plasma, heparinized blood, etc.) 3401. In someembodiments the source of bodily fluid 3401 may be a flask, a beaker, ahuman being or a part of a human being, an animal or a part of ananimal. In the experimental set-up illustrated in FIG. 34A, bodily fluidis circulated substantially continuously from the source to an analytemonitoring system and back to the source 3401 through one or morepatient connectors 3402, 3403 and 3404. FIG. 34B shows the internal viewof one of the patient connectors 3402, 3403 and 3404 afterre-circulating heparinized blood through it for approximately 60 hours.From FIG. 34B, it is apparent that there is no fluid accumulation in theinterior of the patient connector.

The ability of the patient connector to prevent or substantially reduceseparated flow was also tested using animal studies. In one embodimentof the study an animal (e.g. a sheep or a pig) or part of the animal wasused as the source of bodily fluid. Bodily fluid was circulated from theanimal or part of the animal to an analyte monitoring system and back tothe animal or part of the animal through one or more patient connectorsincluding a flow director. It was observed that even after approximately6 hours of continuously circulating bodily fluid, the patient connectorsshowed no accumulation of bodily fluid or clots, thereby demonstratingthe ability of the patient connector to prevent or substantially reduceseparated flow. FIG. 35 shows the experimental setup for one such studyperformed wherein the source of bodily fluid was a vein in a pig's ear.In one embodiment, a catheter (e.g. 20 Ga. peripheral catheter)comprising a patient connector including a flow director was attached toa vein in the pig's ear. An analyte monitoring system substantiallycontinuously withdrew bodily fluid from the vein through the catheter,analyzed the bodily fluid and returned the unused bodily fluid to thepig's ear. The patient connector showed no clots or clogged regionsafter approximately 6 hours of operation.

Self-Adjusting Patient Connector

In various embodiments, tubes or lines (e.g., the patient tube 512 ofthe monitoring device 102 illustrated in FIG. 5) may be joined to othertubes or lines (e.g. a central venous catheter (CVC) or a peripherallyinserter central catheter (PICC) attached to the patient) via a standardconnector (e.g. a standard Luer connector) that includes matchingfittings on the ends of the tubes to be joined. The standard connectorsmay conform to standards that have been developed to permitcompatibility and standardization of commonly-used medical devices. Anexample of specifications for fittings used for medical applications maybe found, for example, in the International Standard ISO 594 titled“Conical fittings with 6% (Luer) Taper for syringes, needles and certainother medical equipment,” and referred to herein as the “ISO LuerStandard.” Fittings meeting the ISO Luer Standard are referred to hereinas “Luer fittings.”

While standards, such as the ISO Luer Standard, provide a framework forproducing interchangeable and/or compatible connectors, the internalvolume and/or shape of the internal volume within fittings may varybetween interchangeable and compatible—but non-identical—fittings. Thisvariation may present problems for low flow or low volume systems, orfor systems benefitting when fluid within connectors is exposed to onlysmooth surfaces. In addition, dead space can sometimes be a problem inlines that are used to provide patients with medication. As used herein,the term “dead space” is a broad term and is used in accordance with itsordinary meaning to refer to any unwanted or unproductive areas that donot allow efficient and/or smooth fluid flow. For example, a widenedportion, a peripheral opening or cavity that is located out of a mainfluid flow path can be “dead space” because fluid can get caught in thatspace and either form eddy currents, turbulence, or stagnation. If aline with a connector having dead space is used to provide a patientwith medication, some of the medication may remain trapped in the deadspace. If the line is later flushed with saline, unknown and potentiallydangerous amounts of the medication may be flushed from the dead spaceand infused into the patient. In an extreme case, this may ultimately bedeadly.

For example, in medical systems and devices used in hospitals it can beuseful to use anticoagulants (e.g. heparin) to help prevent depositsfrom building up in fluid systems, especially those that contain bodilyfluids such as blood. In some medical devices connected to thevasculature of a patient, anticoagulants (e.g., heparin) can be used toprevent blood clotting in a patient and/or to keep the fluid lines open(e.g., by preventing fluids from coagulating in dead spaces ofconnectors). However, if excessive amounts of these anticoagulants areinfused into a patient—for example, when the line is flushed—the patientmay lose some clotting capability and Heparin Induced Thrombocytopenia(HIT) can result in many or all heparin-sensitive patients. HIT can be avery dangerous condition, and may lead to loss of vision, loss of alimb, or even death. Systems and methods of preventing accidentalinjection into the patient are described in U.S. patent application Ser.No. 12/123,422, the publication of which is incorporated by referenceherein in its entirety. Another approach of preventing infusion ofheparin into a patient is to avoid the use of anticoagulants (e.g.heparin) in portions of devices that may be connected to or in fluidcommunication with a patient's vasculature. However, not usinganticoagulants can result in connectors attached to a patient'svasculature being blocked over time due to clotting and/or accumulationof deposits—e.g., in dead spaces and junctions of the connector.

For at least these reasons there is a need for connectors that canprovide a continuous flow path between connecting tubes, through theconnector, with minimized change in the cross-sectional area of variouspoints along the flow path and with reduced dead space. Such connectorscan promote smooth flow and reduce unwanted turbulence and stagnation influid systems, leading to reduced medical risk. Such connectors may havecoatings on the inner or outer walls of the connecting tubes. Thecoatings can be designed to provide a clinical benefit (e.g., deliveringtherapeutic compounds to the fluid flowing through the connector); theycan provide a mechanical benefit (e.g., reducing friction and improvingfluid flow or protecting the sidewall materials from prolonged contactwith the fluid flowing through the connector); and/or they can providesafety and efficiency benefits (e.g., decreasing the probability ofblood clotting and lengthening the useful life of the connector and/or afluid handling system such as may be included in a removable cartridge).

Various embodiments of Standard Luer connectors that are modified tohave reduced internal volume were described in U.S. Publication No.2008/0284167 which is incorporated by reference herein in its entirety.In certain embodiments described in U.S. Publication No. 2008/0284167,the coupled fittings present a nearly uniform flow diameter along forfluids within the fitting.

Some embodiments disclosed herein describe self-adjusting and/oruniversal patient connectors that have very little dead space volume andthat can mate with the base of a catheter (e.g. a CVC or a PICC) hub.FIGS. 36A and 36B disclose examples of a self-adjusting and/or universalpatient connector 3600 that comprise a spring loaded self-adjustingextending tip. As used herein, the term “universal” is a broad term andis used in accordance with its ordinary meaning to describe any devicethat is widely compatible with other devices or that can adjust oraccommodate to various shapes and/or mate with various devices. Justbecause a device may not be configured to mate with every possiblecounterpart does not mean it is not “universal.” The self-adjustingand/or universal patient connector 3600 is configured to connect a fluidline 3601 (which may come from a medical device or system such as amonitoring device 102, e.g., the OPTISCANNER™) to an extender tube 3602which in turn can connect to a fluid line (e.g. a single lumen or amulti lumen CVC or a PICC line, not shown in FIG. 36A or 36B) attachedto a patient. In some implementations, the connector can be reversed andbe oriented in the opposite manner, such that the extender tube 3602generally protrudes toward a medical device and away from a patient.

The extender tube 3602 can be configured and constructed in such a wayas to withstand pressures of 20 psi. In some embodiments, the extendertube 3602 can be configured and constructed in such a way as towithstand pressures less than or greater than 20 psi. The thickness andconstruction of the material of the extender tube walls allow it towithstand pressure in the fluid lines. Moreover, a spring (discussedbelow) can urge the extender tube 3602 into position and that spring canalso assist the extender tube to prevent leaks from internal pressure.

FIGS. 36C, 36D, and 36E show partial section views of embodiments havingdifferent tip characteristics, and how tips can approach and/orinterface with portions of another connector. In various embodiments,the extender tube 3602 can end abruptly as if it were cleanly andperpendicularly sliced to form a flat or “square” tip. A square orflattened tip can provide a convenient shape to allow the extender tube3602 to effectively abut another tube (e.g., if the other tube also hasa square face 3616 b tip as shown on the tubes 3608 in FIGS. 36D-36E).In some embodiments, the second end of the tube 3602 can graduallydiminish in diameter to form a relatively long, sharp, or “tapered” tip(see the tubes 3602 in each of FIGS. 36C-36E for examples of taperedtips, either having frustoconical portions, beveled portions, or both).In some embodiments, the second end of the tube 3602 can be partlytapered but with a blunted or flattened extreme face 3614 b as shown inFIG. 36D. In various embodiments the extender tube 3602 can be beveledat its edge to form a flat face 3614 a, 3614 c that may or may not beconfigured to conform to, insert into, directly abut, or otherwiseinterface with another tube 3608 as shown in FIGS. 36C and 36E. In someembodiments, the extender tube 3602 can comprise a conical tip forsmooth insertion partially into another tube (see FIGS. 36D and 36E forexamples of partly conical tips). The interface between tubes 3608 and3602 can also be configured with one face convex and the other concave,and/or with one having a protrusion and the other having a complementaryopening. Various combinations of tip shapes can be configured to form agood seal and allow smooth flow between adjacent tubes.

In some embodiments, a universal connector is designed to interface withvarious existing and commonly-used connectors. In FIGS. 36C-36F, forexample, a mating connector 3612, a tube 3608, and a Luer base 3604 cantogether represent an existing device that is commonly used in medicalsettings, for example. Referring to FIG. 36F, these structures can bereferred to together as a “standard” connector. But connecting twostandard connectors together can have a drawback of allowing fluid toflow, out of a tube 3608 and into a portion having a wider cross-sectionthat may include side regions or “dead space” 3617. This dead space 3617can inhibit smooth flow and allow unwanted pooling, stagnation, and whenblood is involved, clotting.

Embodiments herein can provide a penetrating connector having anextender tube 3602 that can be positioned along a fluid line (e.g., theline comprising the tube 3608 and the fluid line 3601) between a medicaldevice and a source of body fluid to allow fluid flow while reducingleaks. Reducing leaks can involve pressure containment such as, forexample, preventing fluid from escaping when the internal fluid pressureis less than 20 psi. The penetrating connector can have openings ateither end (see, e.g. the receiving opening 3634 discussed further belowwith respect to FIG. 36G, and the opening at the other end in thegeneral vicinity of reference numeral 3626 b of FIG. 36G) that cooperatewith openings of other connecting devices and/or fluid lines to assistin forming mating complexes (e.g., the structures illustrated in FIGS.36C-36E and/or FIGS. 37A-37H) at either end of the connector. The matingcomplexes can include an enlarged space (e.g. the dead space 3617 shownin FIG. 36F). The extender tube 3602 can penetrate into an opening in astandard connector or one of the mating complexes as suggested by arrow3619, and it can bypass dead space 3617, thereby confining fluid withinits walls to prevent the fluid from flowing out into the enlarged space(e.g., the dead space 3617) of the mating complex. The extender tube canphysically contact either the side-walls 3618 of the mating connector3612, or the tube 3608, or both. The penetration of the extender tube3602 along the path of the arrow 3619 can be provided either by theforce of a health care provider putting two connectors together or by aforce-exerting structure (e.g. a spring) or other resilient mechanism.The force-exerting structure can use a resilient property to improve aseal between the extender tube and the opening in the standard connectoror another medical device. The force-exerting structure can comprise oneor more of the following: a spring 3605; a hub 3606; an extender tube3602 with a stiff tip; an extender tube 3602 with a stiff body; aback-up ring 3609, an O-ring 3607; an inner portion of a matingconnector 3612; a tube 360; a surface 3618 or some other portion of amating connector 3612; or some combination of the above.

With further reference to FIG. 36F and with the understanding that anextender tube 3602 can be inserted as shown with arrow 3619, in order toachieve a good seal between an extender tube 3602 and the portion of thestandard connector contacted by that extender tube 3602—thereby reducingleakage such as into a dead space 3617—the extender tube 3602 or aportion thereof can be relatively more or less resilient (or converselyrelatively more or less stiff) than the material with which it isdesigned to come in contact. Moreover, the extender tube 3602 that canbe inserted along the path of the arrow 3619 can have a complementaryshape to improve the seal and the flow of fluid between the two tubes3602 and 3608. Various embodiments of a universal connector can comprisea structure having stiffness that is sufficient to resist deformationwhen the universal connector is pushed or urged into position in orderto connect to another connector (e.g. a standard connector having afluid line such as the tube 3608 that may be attached to a patient) ortube. The presence of the stiff structure (combined with complementaryproperties of a material to be contacted) can also aid in forming a goodseal with the other tube and allow smooth fluid flow across the junctionbetween the universal connector and the other (e.g., a standard)connector. In some embodiments, if the connector (e.g. the surface 3618)or tube (e.g. the tube 3608) that is to mate with a universal connectoris very stiff then the universal connector can include components (e.g.an O-ring, a spring, an extender tube, etc.) that are comparatively lessstiff.

Without subscribing to any particular theory, generally resilienceand/or stiffness of any structure are properties that can depend on thematerial, geometry of the structure and boundary conditions that existwhen the structure is brought into contact with another structure.Accordingly, the stiffness-providing or resilience-providing structureof the universal connector can comprise a material having a sufficientmodulus of rigidity (or elasticity) or having a shape that resists orallows deformation. In some embodiments of a universal connector, anextender tube 3602 can be formed from a relatively stiff material thatcan be urged into contact with a surface 3618 or a tube 3608 with aspring 3605 (see FIG. 36B). Stiffness and/or resiliency can be providedboth by the materials and/or shape of a standard connector (see FIG.36F), the materials and/or shape of an extender tube 3602; the materialsand/or shape of a combination of the spring 3605 and the extender tube3602, etc. The stiffness of the spring 3605 or the extender tube 3602can also vary to account for the expected material and geometry of themating connector 3612 or tube 3608. Useful materials includepolyvinylchloride (“PVC”—less stiff) and polyimide (more stiff).

As an example, in some embodiments, the extender tube 3602 can bestiffer than the mating connector (e.g. mating connector 3612 shown inFIGS. 36C-36E) or the tube included within the mating connector (e.g.tube 3608 shown in FIGS. 36C-36E). As another example, the extender tube3602 can be stiffer than the inner walls of the mating connector (e.g.inner wall 3618 shown in FIG. 36F). In some embodiments, the extendertube 3602 can comprise a material that is stiffer (and/or has a highermodulus of elasticity) than the material of the fluid line 3601, thematerial of the mating connector 3612 of FIGS. 36C-36E and/or thematerial of the tube 3608 of FIGS. 36C-36E. As an example, the extendertube can comprise a stiff material such as polyimide that can be stifferthan PVC. In some variations of the universal patient connector, theextender tube can comprise a stiffer material at its extremity while theremaining portion of the extender tube 3602 can comprise a less stiffmaterial. In some embodiments, the portion of the extender tube 3602that extends beyond the patient connector can comprise a stiffermaterial while the portion of the extender tube that is within thepatient connector can comprise a less stiff material. In someembodiments, the extender tube 3602 can be stiffer or less resilientthan the spring 3605. However, the spring 3605 can provide support tothe extender 3602 and can assist the extender tube 3602 in pushingagainst the mating materials (e.g., the tube 3608, the mating connector3612, etc.) Indeed, the spring 3605 can itself be relatively stiff,while still providing resiliency.

With further reference to FIG. 36A, a spring housing 3603 can surround aportion of the fluid line 3601 and connect to a standard Luer base 3604that is configured to mate with standard Luer connections. The standardLuer base 3604 can thus provide a sturdy physical connection on theoutside, while the spring housing can provide a frame against which aninternal spring can push, urging the protruding end of the extender tube3602 into a smoother and more immediate mating relationship with anotherconnector. The extender tube 3602 can thus allow fluid to bypass anydead space that may otherwise exist in the Luer connection and flowdirectly into a downstream (or upstream) connector.

The connector 3600 (including the standard Luer base 3604 and the springhousing 3603, for example), can be configured and constructed in such away as to withstand (e.g., contain while reducing or preventing leaks)pressure of 100 psi. The thickness and construction of the material ofthe connector walls can allow it to withstand pressure in the fluidlines. The line pressure at the connector can vary depending on backpressure (e.g., blood pressure) and the type of catheter to which theconnector 3600 may be attaching. In a common implementation, thepressure within an assembled connector 3600 can be approximately 1.5 psiabove the back pressure.

FIG. 36B illustrates an exploded view of the universal and/orself-adjusting patient connector 3600. The universal and/orself-adjusting patient connector comprises a spring housing 3603 whichhouses a spring 3605. In various embodiments, the fluid line 3601 isinserted through the spring housing 3603 and the spring 3605 and meetsup with or connects to a first end of an extender tube 3602. A secondend of the tube 3602 extends into a standard Luer base 3604. In variousembodiments, an O-ring 3607 and a back-up ring 3609 can encircle theextender tube 3602 and be generally disposed between the spring housing3603 and the Luer base 3604. In various embodiments, the first end ofthe extender tube 3602 can seat against a hub 3606 which intervenesbetween the fluid line 3601 and the extender tip 3602. The hub 3606 canhave a passage that smoothly changes diameter, if warranted, between theinner diameter of the fluid line 3601 and the inner diameter of theextender tube 3602, thus providing a continuous flow path with minimalcross sectional area change and minimizing dead volume. The extendertube 3602 (which can be referred to as a spring loaded self-adjustingextender tube, for example) can also maintain relatively uniformvelocity of the fluid across the patient connector. Maintaining uniformvelocity across the connector can provide the following advantages: (a)rapid flushing fluid line 3601 and/or tube 3603; (ii) reducing oreliminating trapped bubbles; (iii) reducing or eliminating bloodclotting that may otherwise occur in a patient connector.

A universal and/or self-adjusting patient connector, in a generalizedform, can be illustrated as shown in FIG. 36G. The connector cancomprise a standard-facing end 3626 (e.g., an end configured to matewith a standard male or female Luer connector) that can include astandard-facing outer portion 3626 a and a standard-facing inner portion3626 b that comprises an extended flow passageway 3622. The connectorcan further include an opposite end 3627 having an opposite outerportion 3624 comprising a first pushing surface 3632 and a receivingopening 3634 configured to receive a regular flow passageway 3620. Invarious embodiments, the standard-facing outer portion 3626 a and theopposite outer portion 3624 together comprise an outer housing 3629. Theconnector further comprises a second pushing surface 3636 facing thefirst pushing surface 3632. The extended flow passageway 3622 isconfigured to connect to the regular flow passageway 3620 to form acombined flow passageway configured to move with the second pushingsurface 3636. A force-exerting member or an actuating member 3628 (e.g.a spring) is situated between the first pushing surface 3632 and secondpushing surface 3636 and that actuating member 3628 is configured tosimultaneously exert a force against both of these pushing surfaces tothereby urge the first pushing surface 3632 (along with the outerhousing 3629) away from the second pushing surface 3636 (along with thecombined flow passageway), thereby causing the extended flow passageway3622 to approach—and the inner portion 3626 b of the standard-facing endto more firmly seat against—an inner portion of any of a variety ofstandard connectors having different depths. In this context, it can beunderstood that a generalized embodiment can include a universalconnector with an outer portion (e.g., the housing 3629 and inparticular the standard-facing outer portion 3626) that can connectrelatively firmly to a standard connector. This relatively firmconnection can occur using a threaded luer lock, for example. Thegeneralized embodiment can also have an inner portion (e.g., theextended flow passageway 3622) that can connect relatively firmly to aflow passageway (e.g., the regular flow passageway 3620). Thisrelatively firm connection can occur using a connecting hub and/oradhesive, for example. At the same time, the generalized embodiment caninclude a resilient (as opposed to a relatively firm) connection betweenthe inner portion and the standard connector, as the embodiment uses thefirst relatively firm connection and its own relatively rigid structureas a base against which to brace as it urges the inner portion intocontact with the standard connector.

FIG. 36H illustrates a generalized view of a connector when it is notconnected to or associated with any fluid lines. The connector caninclude an outer portion 3629 comprising at least one standard-facingend 3626; an inner portion 3630 comprising an extended flow passageway3622; and an actuating member 3628 that is situated between the outer3629 and the inner portion 3630 and configured to move the inner portion3630 toward or away from the outer portion 3629 thereby causing theextended flow passageway 3622 to approach and seat against an innerportion of any of a variety of standard connectors (e.g. male or femaleLuer connectors) having different depths.

Analyte monitoring systems can be connected to a source of bodily fluidvia a connector that is configured to reduce blood clotting risk. Bloodclotting risk can be reduced, for example, by employing coatings in oron a connector, by reducing dead space volume in a connector, by usingresiliency to improve fit, by extending a portion of one connector tobetter mate with a portion of another connector, etc.

As discussed above under the heading “SELF-ADJUSTING PATIENT CONNECTOR,”it can be desirable to reduce the amount of dead space in and aroundconnections along a fluid path. Such a reduction of dead space mayreduce turbulence in a flowing fluid, for example. One way to reducedead space is to include a sealing mass at or near an interface wherefluid flows from a tube and into a connector. For example, a sealingmass can be placed on or around a tube that is part of the fluid path.The sealing mass may be placed anywhere along the length of the tube,and may be placed so that it partially or fully surrounds the tube. Thesealing mass may be placed at specific locations along the tube where itmay be most effective in reducing dead space. For example, the sealingmass may be placed such that it encircles a connecting tube near the tipof the connecting tube. Placing a sealing mass which encircles aconnecting tube near the tip of the connecting tube that will connect toanother tube may help reduce dead space at such a connection because thesealing mass can resiliently deform to fill cavities or crevices thatmay otherwise allow fluid pooling, stagnation, eddy currents, etc. Ifthe sealing mass is placed near the tip of a connecting tube for thispurpose, it may be desirable to minimize the distance between thesealing mass and the tip of the connecting tube because fluid may bemore likely to leak out of the tip, so stopping the flow of leaked fluidadvantageously occurs close to the original leak. For example, it may beadvantageous to place a sealing mass within 0.001, 0.005, 0.01, 0.05 or0.1 inches from the tip of a connecting tube. A sealing mass may beplaced on one or both of the tubes that are to be connected. A sealingmass may be especially useful on connectors which are intended to beused multiple times and for multiple fluid cycles.

A sealing mass may be made out of any type of material. The materialused for a sealing mass may be chosen based upon any number of desirablecharacteristics, such as biological neutrality (or biological activity),affinity for the fluid in the fluid path (or lack of affinity),impermeability, resilience, compressibility, cost, ease of manufacture,ease of attaching to a tube, or other reasons. Various approaches canimprove the sealing ability of a sealing mass. For example, a sealingmass may be made from the same type of material as the tube itsurrounds. This can allow the mass and the tube to resiliently abut orconform to other surfaces and to each other in a similar manner. Asealing mass may be joined to the tube it surrounds. This can reduce thelikelihood of fluid leakage between the sealing mass and the tube andalso assist in urging the sealing mass against a mating connector. Ifthe tube has a resilient force (e.g., from a spring) that may be urgingthe tube against a mating surface of another connector, coupling aresilient mass to the tube can cause the resilient force to also urgethe sealing mass against the mating surface or adjacent surfaces. Asealing mass may be a unitary piece with the tube that it surrounds forsimilar reasons. It can be beneficial to make a sealing mass from aresilient or compressible material, as these materials may be useful tomore effectively fill dead space and thereby reduce turbulence in afluid path. These materials, when urged by a tube that has a resilientforce (e.g., from a spring), may form a fluid-tight seal around thefluid path between the connector and a mating connector. In oneparticularly useful example, a sealing mass may be a plug or roughlyfrustoconical body made out of silicone.

If a sealing mass is placed such that it encircles a connecting tubenear a tip of the connecting tube, a resilient or compressible materialcan help to create a seal between the connecting tube and a second tube.Compressible or resilient material may be preferable because suchmaterial may be able to form a tighter or larger seal near theconnection between the connecting tube and the second tube. This tighteror larger seal may restrict a fluid traveling through the tube fromentering dead space that may otherwise be present near the connectionbetween the connecting tube and the second tube. A resilient orcompressible sealing mass placed near the tip of a connecting tube maybe especially effective in forming a tight, large seal in the presenceof a force-exerting or an actuating member. A force-exerting member maybe designed to apply pressure to firmly seat the connecting tube and thesecond tube. Such pressure may be sufficient to partially compress aresilient or compressible sealing mass that encircles the tip of theconnecting tube.

A sealing mass that is placed around a tube may be any shape. The shapeof the sealing mass may depend upon what type of material is used, whereit is placed, and the anticipated use of the sealing mass. For example,if a sealing mass is placed encircling the tip of a tube which willconnect to another tube, this may make some shapes more advantageous. Asealing mass with a radially symmetric shape may be desirable in orderto create a larger or better seal. This can be especially helpful in acommon medical setting where medical connectors (and the female openingstherein) are radially symmetric. Thus, the shape, surface angles, andsymmetries of the sealing mass can be made compatible with a widevariety of possible connectors. If it is known what type of connector atube will connect to, the shape of the sealing mass may be based uponthe shape of the corresponding connector. For example, if thecorresponding connector is a standard female Luer connector, it may beuseful if the sealing mass at the tip of the tube is in a frustoconicalshape or has a generally frustoconical portion. This shape may allow atight seal to be formed between the sealing mass and a correspondingfemale Luer connector, and thereby reduce leakage and/or turbulence atsuch a connection. Such a sealing mass may be extremely useful becauseit is able to be used with a standard connector, rather than requiringcompletely new connectors to be used. A patient connector with a sealingmass may be able to act as a male connector and connect to a standardfemale connector. Alternatively, a patient connector with a sealing massmay be able to act as a female connector and connect to a standard maleconnector. For example, a sealing mass may be placed around aninlet/outlet on a female connector in a location that is configured tocome into contact with a standard male connector when the connectors areattached. Such a sealing mass may take on a shape that is suited to forma seal between the patient connector and the standard male connector.For example, a sealing mass may have an O-shape, designed to encirclethe inlet/outlet that forms an interface with the standard maleconnector. A sealing mass may be created such that a patient connectormay be able to reduce dead space and the incidence of blood clottingwhile working with existing, standard connectors. A sealing mass mayallow a patient connector to be used as a medical device takes multiplesamples of an individual.

FIG. 36I illustrates a generalized view of a patient connector 3652 thatincorporates a sealing mass that can have some of the advantages andincorporate some of the principles discussed above. In this embodiment,an outer housing 3653 is configured to receive a regular flow passageway3651. A connecting tube 3655 is connected to the to the regular flowpassageway 3651 inside the outer housing 3653. The connecting tubeincludes a tip 3657 that is suitable for connecting with anotherconnector which corresponds with the patient connector 3652. A sealingmass 3659 is positioned on the connecting tube 3655 near the tip 3657.The connecting tube 3655 extends through the sealing mass 3659 to thetip 3657.

FIG. 36J illustrates a generalized view of a patient connector 3654 thatincorporates a sealing mass 3667, where the sealing mass 3667 has ashape configured to generally approximate a shape of the interface 3673of the corresponding connector 3671 even when the patient connector 3654is not mating with the corresponding connector. In this embodiment, anouter housing 3675 is configured to receive a regular flow passageway3651. Inside the outer housing 3675, there is a first pushing surface3661 and a second pushing surface 3663, with the regular flow passageway3651 connected to a connecting tube 3655 through the second pushingsurface 3663. A sealing mass 3667 is positioned on the connecting tube3655 near the tip 3657. The connecting tube 3655 extends through thesealing mass 3667 to the tip 3657. A force-exerting member or anactuating member 3665 (e.g., a spring) is situated between the firstpushing surface 3661 and second pushing surface 3663 and that actuatingmember 3665 is configured to simultaneously exert a force on both ofthese pushing surfaces to thereby urge the first pushing surface 3661away from the second pushing surface 3663, thereby pushing theconnecting tube 3655 towards a corresponding connector 3671. Thecorresponding connector 3671 will have an interface 3673. The sealingmass 3667 is configured to generally approximate a shape of theinterface 3673 of the corresponding connector 3671 even when the patientconnector is not mating with the corresponding connector, to allow forthe sealing mass 3667 to minimize the dead space in the connectionbetween the connecting tube 3655 and the corresponding connector 3671.

One or more coatings may be applied to any surface of a patientconnector or an analyte monitoring system. For example, coatings may beapplied to the inner or outer walls of connecting tubes in a patientconnector, on the exterior of a patient connector, on a sealing mass ona patient connector, or any other surface of the patient connector. Suchcoatings may serve any number of purposes, such as making a connectorlast longer, preventing materials used in the connector from enteringthe fluid contained in a fluid path, increasing the accuracy of ananalyte measurement, allowing for more flexibility in which materialsare used in a patient connector, or reducing blood clotting in thepatient connector. The purpose of a coating may determine where on apatient connector the coating is applied. For example, if a coating isdesigned to reduce or eliminate blood clotting in a patient connector,it may be advantageous to apply the coating to the inner and outer wallsof a connecting tube, to a sealing mass placed near the tip of theconnecting tube, and/or to any other surface that blood may come intocontact with. A coating that is designed to reduce or eliminate bloodclotting may be applied to any surface in an analyte monitoring systemthat may come into contact with blood. For example, a coating may beapplied to an analyte monitoring system that is situated outside thebody, either in the analyte monitoring system or in a tube that leads tothe analyte monitoring system. For example, a coating may be appliednear an intersection, such as the first connector 524 (C1) asillustrated in FIG. 5. An intersection such as this may be especiallyprone to turbulence because fluid flowing through the connector may berequired to make a sharp 90-degree turn. Fluid that flows past a firstconnector 524 may be especially prone to turbulence when a valve 531 isclosed, if the valve 531 is some distance away from the first connector524. For example, when valve (e.g., a pinch valve, rotary valve, shuttlevalve, etc.) is placed some distance from an intersection, fluid that isin the tube leading to the closed valve may be more likely to beturbulent. Therefore, to avoid such turbulence, it may be useful toapply a coating to such an intersection, especially when a valve isplaced further away from the intersection. A coating may be applied toan analyte monitoring system that is designed to take multiple readingsof analyte levels. Such a coating may be applied to a connector that isused during multiple readings from a medical device, and over multiplefluid withdrawal cycles. A coating may also be applied to an analytemonitoring system that is situated at least partly inside the body. Acoating may also be applied to other systems that may come into contactwith blood where it is desired to reduce friction and/or avoid bloodclotting.

There are a number of ways that a coating may assist in reducing oreliminating blood clotting in a patient connector. For example,lubricious coatings can be used to reduce friction between the flowingfluid and the side-walls of the connector. Therapeutic drug deliverycoatings can also be used (e.g., drug-eluting coatings). Some usefulcoatings include those that comprise heparin, which can be designed toreduce blood clotting against the side-walls of the connector by actingas an anticoagulant. A coating may be applied to the inner or outerwalls of a connecting tube to reduce friction between a wall of theconnecting tube and blood flowing within the tube. A reduction infriction may reduce the shear stress on blood that flows in a boundaryarea near the side-walls of the connector. The blood coagulation cascadeis a very delicate process, and a reduction in shear stress can decreasethe tendency for blood to begin to coagulate by reducing the turbulencein blood passing through the patient connector. Any number oflubricating agents may be suitable to form a lubricious coating on theinner or outer walls of the connecting tubes. A number of companiesprovide a wide array of active or inactive haemocompatible coatings thatcan be used in this context. Such companies include: AdvanSourcebiomaterials (e.g., HydroMed); AorTech Biomaterials; Applied MembraneTechnology (e.g., Silglide, Fluorocarb); AST Products Inc. (LubriLAST);Bayer (e.g., Baymedix CL); Biocoat, Inc. (e.g., HYDAK); BioInteractionsLtd. (e.g., Assist); Cadence Inc.; Carmeda (e.g., CBAS); Coatings2GoLLC; Covalon Technologies Ltd.; Demax Medical; DSM Biomedical (e.g.,ComfortCoat); Hemoteq (e.g., Lubriteq); Medkote; Merit Medical SystemsInc. (e.g., Endotek); SurModics Inc. (e.g., Rejoice, Harmony); and TegraMedical. Lubricious coatings can be used to coat the inner or outerwalls of the connecting tubes. Lubricious coatings such as this candramatically reduce the friction between blood and the inner walls ofthe connecting tubes, and therefore reduce the shear stress on theblood. Lubricious coatings may be advantageous because they are lesslikely than some other coatings to interfere with analyte detection andmeasurement. Lubricious coatings may also be easier to apply to theinner and outer walls of a connecting tube, and may be morecost-effective than other types of coatings. Lubricious coatings mayalso present less danger than some types of drug-eluting coatings (asdiscussed above under the heading “SELF-ADJUSTING PATIENT CONNECTOR,”and therefore be easier to work with or more desirable than other typesof coatings. Lubricious coatings can work with a patient connectordesign that minimizes dead space to reduce the incidents of clottingthat are seen in the inner walls of the connecting tubes. It may benecessary to apply such a coating to a patient connector or other deviceas one of the later steps in production, as coatings may be somewhatmore sensitive to temperatures encountered during manufacturing. Forexample, it may be desirable to apply a coating to a patient connectoras a final step in manufacturing a patient connector, to ensure that theheat needed to shape the patient connector does not adversely affect thecoating and inhibit its function.

Coatings may reduce the need for detergent and/or heparin to flush thefluid system between draws and may allow for more frequent measurements.For example, a lubricious coating may ensure that less blood or otherfluid remains in the fluid system after blood is drawn. If less bloodremains in the fluid system after blood is drawn, this may reduce theamount of detergent and/or heparin (such as tergazyme A) that are neededto flush the system between blood draws. This may simplify the design ofthe system, may create less waste, and/or may make the system lessexpensive to create and to operate. Coatings may also allow for morefrequent measurements, as less time may be needed between eachmeasurement to flush the system and the system could be flushed moretimes with the same quantity of detergent and/or heparin.

FIG. 36K illustrates a cross-section view of a sealing mass 3675 that ispositioned on a connecting tube 3655 near the tip 3657 of the connectingtube 3655. The sealing mass 3675 may have a frustoconical shape in aregion 3679 that is near the tip 3657 of the connecting tube 3655. Theremainder 3677 of the sealing mass 3675 may also have a frustoconicalshape, although it may be less pronounced than the frustoconical shapein a region 3679 that is near the tip 3657 of the connecting tube 3655.The distance 3681 between the sealing mass 3655 and the tip 3657 of theconnecting tube 3655 may be configured to be very small, thereby placingthe sealing mass 3675 in close proximity to the tip 3657 of theconnecting tube 3655. For example, the distance 3681 between the sealingmass 3655 and the tip 3657 of the connecting tube 3655 may be 0.001,0.005, 0.01, 0.05 or 0.1 inches. It may also be beneficial to apply acoating to portions of the connecting tube 3655 and sealing mass 3675.For example, a coating may be applied to the inner walls 3683 of theconnecting tube 3655, to the tip 3657 of the connecting tube 3655, or toany part of the sealing mass 3675.

FIG. 36L illustrates a different view sealing mass 3675 from FIG. 36K.In this head-on view, the sealing mass 3675 encircles the tip 3657 ofthe connecting tube. This views helps to illustrate the radial symmetrythat a sealing mass 3675 may possess. This radial symmetry may allow asealing mass 3675 to form a tighter, larger seal with a matingconnector. A sealing mass 3675 may have a frustoconical shape in aregion 3679 that is near the tip 3657 of the connecting tube. Theremainder 3677 of the sealing mass 3675 may also have a frustoconicalshape, although it may be less pronounced than the frustoconical shapein a region 3679 that is near the tip 3657 of the connecting tube. Itmay be beneficial, as before, to apply a coating to the tip 3657 of theconnecting tube, as well as to the sealing mass 3675.

FIG. 36M illustrates a view of a patient connector 3685 that includes asealing mass 3687. The sealing mass 3687 may encircle a connecting tube3689 near the tip 3691 of the connecting tube 3689. The tip 3691 of theconnecting tube 3689 may be configured to adjustably accommodate andfirmly abut a mating connector. The sealing mass 3687 may be made of aresilient material (e.g., silicone) so that when the tip 3691 of theconnecting tube 3689 firmly abuts a mating connector, the sealing mass3687 may create a seal with the mating connector around a fluid flowinside the connecting tube 3689. The patient connector 3685 may have anouter housing 3693. The outer housing 3693 may have threads 3695, whichmay be used to attach the patient connector 3685 to a mating connector(not shown).

FIG. 36N illustrates a view of a patient connector 3686 that includes asealing mass 3688. The sealing mass 3688 may be made out of silicone, oranother resilient material. The sealing mass 3688 may encircle aconnecting tube 3690 near the tip 3692 of the connecting tube 3690. Itmay be beneficial to apply a coating to an inner portion of theconnecting tube 3690, to the tip 3692 of the connecting tube 3690,and/or to a portion of the sealing mass 3688. The patient connector 3686may have an outer housing 3694. The outer housing may have threads 3696,which may be used to attach the patient connector 3686 to a matingconnector.

In testing on sheep, placing a silicone sealing mass around the tip of atube and coating the inner walls of the connecting tubes with alubricious or heparin coating has been shown to significantly increasethe length of time it takes before clotting is observed in aself-adjusting patient connector such as those described herein. Aseries of tests have been conducted, which show the efficacy of someembodiments at reducing the frequency of blood clotting. In each test, acatheter was attached to a sheep, and was used to draw blood every 15minutes for the duration of the test. The blood drawn from the sheepflowed through a self-adjusting patient connector. In each test, theamount of time it took to withdraw a certain amount of blood wasrecorded, and this time was used to determine whether any anti-clottingmeasures were successful. A connector that is able to prevent bloodclotting should ensure that successive blood draws will not take moretime than previous blood draws through the same system. If a blood drawthrough the same system takes substantially longer than a previous blooddraw, this may be a sign that a clot has begun to form within theconnector.

In a first test, a sheep was attached to both a peripheral venouscatheter (PVC) and a central venous catheter (CVC) using aself-adjusting patient connector without any coating or sealing mass todetermine how long it would take for blood clots to form within theconnector. In this test, clotting developed in the PVC after 3.4 hours,and clotting developed in the CVC after 5.6 hours. The results of thistest may suggest a 10- to 12-hour useful life for human patients. In asecond test, two different coatings were used on the inner and outerwalls of the connecting tubes. Although the coatings used for this testhappened to be the SurModics Rejoice Passive Hemocompatible Coating, alubricious coating, and the SurModics Applause Heparin Coating, adrug-eluting coating, many other coatings can be used; see supra for anon-exhaustive partial list of example coating sources and coatings. Inthis second test, a sheep was attached to a CVC for 12 hours, to testboth the lubricious and the drug-eluting coatings. During the 12 hourduration of the test, neither connecting tube showed any sign ofclotting. Therefore, it appears that either a drug-eluting or alubricious coating may be effective in reducing the frequency of bloodclotting in fluid systems. In a third test, a lubricious coating wasapplied to the walls of the connecting tubes, and a silicone sealingmass was placed near the tip of the connecting tube. Although thelubricious coating used here was the SurModics Rejoice PassiveHemocompatible Coating, many other coatings could have been used; seesupra for a non-exhaustive partial list of example coating sources andcoatings. In this test, a patient connector was attached to a sheepthrough a CVC for 36 hours. During the 36 hours of this test, noclotting was observed. In a fourth test, three connecting tubes wereused, each with a silicone sealing mass and each coated with alubricious coating. Although the lubricious coating used here was theSurModics Rejoice Passive Hemocompatible Coating, many other coatingscould have been used; see supra for a non-exhaustive partial list ofexample coating sources and coatings. The connecting tubes were attachedto a sheep through a CVC for 42 hours. A measurement was taken for eachblood draw from the fourth test, to determine the length of time thateach blood draw took. Throughout the duration of the test, for each ofthe three self-adjusting patient connectors, each blood draw took a veryconsistent amount of time, between 35 and 45 seconds. No clotting wasobserved in any of the three self-adjusting patient connectors in thistest.

In a fifth test, a 72-hour study was conducted using three connectorsattached to two sheep. This test used patient connectors with alubricious coating and silicone sealing masses. Although the lubriciouscoating used here was from SurModics, many other coatings or supplierscould have been used; see supra for a non-exhaustive partial list ofexample coating sources and coatings. In this test, one patientconnector was able to successfully last 72 hours without any clotsforming. The other two patient connectors were also able to last a longtime before blood clots appeared, with the connectors lasting for 47 and53 hours. It is possible that these connectors may have lasted evenlonger if the lubricious coating was applied to additional parts of theconnector or an analyte monitoring system. In this way, these connectorsmay extend the length of time that a medical device connector can beused for repeated blood withdrawal. For example, these connectors areable to allow at least 12 hours of repeated blood draws without clotformation, whereas prior connectors suffered from clot formation infewer than 6 hours.

In various embodiments, the patient connector can include fittings andlock assemblies that comply with ISO 594/1 and ISO 549-2 standards. Invarious embodiments, the patient connector can be configured andconstructed to withstand up to and beyond 5 times normal operatingpressure. As discussed above, various embodiments of the patientconnector described herein can easily withstand about 1.5 psi over theback pressure. Back pressures can vary widely and can be correlated to apatient's blood pressure, for example. Normal arterial blood pressurescan be in the range of 112/64 mmHg (˜2.17/1.24 psi), but diastolicpressures can be <60 mmHg (˜1.16 psi) or >100 mmHg (˜1.93 psi), andsystolic pressures can be <90 mmHg (˜1.74 psi) or >160 mmHg (˜3.09 psi).Venous blood pressures can often be lower than arterial pressures. Invarious embodiments, the patient connector can be configured andconstructed to withstand back pressures higher than the values mentionedabove. For example, the connector can be useful to connect to differentmedical devices that do not have arterial or venous pressures butinstead have pressures that are induced by pumps, gravity, and otherdevice parameters.

The patient connector 3600 can be compatible with a wide variety of CVCsand PICCs with depths ranging from approximately 0.270″ to approximately0.780″ (approximately 6.9 mm to approximately 19.8 mm) and diameters upto 16 gauge (5 Fr). For example, FIG. 37A illustrates a cross-sectionalview of the patient connector 3700 configured to connect a patient tube3701 to an 18 ga CVC having a tapered tip. A first end of the extendertube 3702 a connects to the patient tube 3701 via a hub 3706. The secondend of the extender tube 3702 a is tapered and connects to the 18 ga CVChaving a tapered tip. As discussed above with reference to FIG. 36A, an“O-ring” may be disposed between the extender tube 3702 a and the Luerbase 3704. A standard Luer fitting 3708 that is matched to the Luer base3704 can include a fluid line (e.g. a CVC or a PICC line) that isattached to the patient. In the embodiment illustrated in FIG. 37A, theLuer base 3704 is configured to match to a COOK type male Luer fitting3708.

FIG. 37B illustrates a cross-sectional view of the patient connector3700 configured to connect a patient tube 3701 to an 18 ga CVC having asquare tip. In the embodiment illustrated in FIG. 37B, the second end ofthe extender tube 3702 b is square. Similar to FIG. 37A, the Luer base3704 is configured to match to a COOK type male Luer fitting 3708.

FIG. 37C illustrates a cross-sectional view of the patient connector3700 configured to connect a patient tube 3701 to an 18 ga PICC linehaving a tapered tip. In the embodiment illustrated in FIG. 37C, thesecond end of the extender tube 3702 c is tapered. In the embodimentillustrated in FIG. 37C, the Luer base 3704 is configured to match to aBD type male Luer fitting 3708.

FIG. 37D illustrates a cross-sectional view of the patient connector3700 configured to connect a patient tube 3701 to an 18 ga CVC having atapered tip. In the embodiment illustrated in FIG. 37D, the second endof the extender tube 3702 d is tapered. In the embodiment illustrated inFIG. 37D, the Luer base 3704 is configured to match to an Arrow typemale Luer fitting 3708.

FIG. 37E illustrates a cross-sectional view of the patient connector3700 configured to connect a patient tube 3701 to a 20 ga PICC linehaving a tapered tip. In the embodiment illustrated in FIG. 37E, thesecond end of the extender tube 3702 e is tapered. In the embodimentillustrated in FIG. 37E, the Luer base 3704 is configured to match to aJohnson & Johnson type male Luer fitting 3708.

FIG. 37F illustrates a cross-sectional view of the patient connector3700 configured to connect a patient tube 3701 to an 18 ga PICC linehaving a square tip. In the embodiment illustrated in FIG. 37F, thesecond end of the extender tube 3702 f is square. In the embodimentillustrated in FIG. 37F, the Luer base 3704 is configured to match to aBD type male Luer fitting 3708.

FIG. 37G illustrates a cross-sectional view of the patient connector3700 configured to connect a patient tube 3701 to an 18 ga CVC having asquare tip. In the embodiment illustrated in FIG. 37G, the second end ofthe extender tube 3702 g is square. In the embodiment illustrated inFIG. 37G, the Luer base 3704 is configured to match to an Arrow typemale Luer fitting 3708.

FIG. 37H illustrates a cross-sectional view of the patient connector3700 configured to connect a patient tube 3701 to a 20 ga PICC linehaving a square tip. In the embodiment illustrated in FIG. 37H, thesecond end of the extender tube 3702 h is square. In the embodimentillustrated in FIG. 37H, the Luer base 3704 is configured to match to aJohnson & Johnson type male Luer fitting 3708.

To understand and evaluate the performance of an example self-adjustingpatient connector, and the compatibility of the various embodiments ofthe self-adjusting patient connector with other connectors, 12 healthydiabetic patients were connected to a medical device (e.g. theOPTISCANNER™) including an embodiment of the self-adjusting patientconnector at its end for a period of about 74 hours. The other end ofthe self-adjusting patient connector was connected to a peripheral IV ineach of the 12 patients. As illustrated in FIG. 38A, the self-adjustingpatient connector 3800 included an extender tube 3802 and a spring (notshown) which maintained the structural integrity of the extender tube3802 and the connector 3800 under constant spring force. The extendertube 3802 included polyimide for additional structural stability. As canbe seen from FIGS. 38A and 38B, even after approximately 24 hours ofoperation (e.g. 23 hours 30 minutes), the fluid flow path in theextender tube 3802 remained open and was not clogged or occluded due toclotting of the blood. Additionally, FIGS. 38A and 38B illustrate thatthe extender tube maintained its shape even after approximately 24 hoursof operation and that the extremity of the extender tube was notdeformed.

The self-adjusting patient connector was also tested for compatibilitywith various catheters. It was found that the self-adjusting patientconnector was compatible with a BBraun Vasofix peripheral catheter aswell as BD Angiocath Autogard catheter. FIG. 38C illustrates theself-adjusting patient connector 3800 connected to a BBraun Vasofixperipheral catheter.

In another test, a medical device (e.g. the OPTISCANNER™) including anembodiment of the self-adjusting patient connector at its end wasconnected to a proximal port of a femoral venous catheter (e.g. Arrowtriple lumen catheter) of a patient in the ICU for 12 hours. As seenfrom FIG. 39, even after 12 hours of continuous operation, the fluidflow path in the extender tube 3902 remained open and was not clogged oroccluded due to clotting of the blood. The extender tube or theself-adjusting connector was not manually primed at any point duringthis test. The above tests indicate that some embodiments of theself-adjusting patient connector can be used over longer periods of timewithout requiring replacements due to structural deformation orocclusion of the fluid flow path as compared to other standardconnectors.

Reference throughout this specification to “some embodiments” or “anembodiment” means that a particular feature, structure or characteristicdescribed in connection with the embodiment is included in at least someembodiments. Thus, appearances of the phrases “in some embodiments” or“in an embodiment” in various places throughout this specification arenot necessarily all referring to the same embodiment and may refer toone or more of the same or different embodiments. Furthermore, theparticular features, structures or characteristics may be combined inany suitable manner, as would be apparent to one of ordinary skill inthe art from this disclosure, in one or more embodiments.

As used in this application, the terms “comprising,” “including,”“having,” and the like are synonymous and are used inclusively, in anopen-ended fashion, and do not exclude additional elements, features,acts, operations, and so forth. Also, the term “or” is used in itsinclusive sense (and not in its exclusive sense) so that when used, forexample, to connect a list of elements, the term “or” means one, some,or all of the elements in the list.

Similarly, it should be appreciated that in the above description ofembodiments, various features are sometimes grouped together in a singleembodiment, figure, or description thereof for the purpose ofstreamlining the disclosure and aiding in the understanding of one ormore of the various inventive aspects. This method of disclosure,however, is not to be interpreted as reflecting an intention that anyclaim require more features than are expressly recited in that claim.Rather, inventive aspects lie in a combination of fewer than allfeatures of any single foregoing disclosed embodiment.

Embodiments of the disclosed systems and methods may be used and/orimplemented with local and/or remote devices, components, and/ormodules. The term “remote” may include devices, components, and/ormodules not stored locally, for example, not accessible via a local bus.Thus, a remote device may include a device which is physically locatedin the same room and connected via a device such as a switch or a localarea network. In other situations, a remote device may also be locatedin a separate geographic area, such as, for example, in a differentlocation, building, city, country, and so forth.

Methods and processes described herein may be embodied in, and partiallyor fully automated via, software code modules executed by one or moregeneral and/or special purpose computers. The word “module” refers tologic embodied in hardware and/or firmware, or to a collection ofsoftware instructions, possibly having entry and exit points, written ina programming language, such as, for example, C or C++. A softwaremodule may be compiled and linked into an executable program, installedin a dynamically linked library, or may be written in an interpretedprogramming language such as, for example, BASIC, Perl, or Python. Itwill be appreciated that software modules may be callable from othermodules or from themselves, and/or may be invoked in response todetected events or interrupts. Software instructions may be embedded infirmware, such as an erasable programmable read-only memory (EPROM). Itwill be further appreciated that hardware modules may be comprised ofconnected logic units, such as gates and flip-flops, and/or may becomprised of programmable units, such as programmable gate arrays,application specific integrated circuits, and/or processors. The modulesdescribed herein are preferably implemented as software modules, but maybe represented in hardware and/or firmware. Moreover, although in someembodiments a module may be separately compiled, in other embodiments amodule may represent a subset of instructions of a separately compiledprogram, and may not have an interface available to other logicalprogram units.

In certain embodiments, code modules may be implemented and/or stored inany type of computer-readable medium or other computer storage device.In some systems, data (and/or metadata) input to the system, datagenerated by the system, and/or data used by the system can be stored inany type of computer data repository, such as a relational databaseand/or flat file system. Any of the systems, methods, and processesdescribed herein may include an interface configured to permitinteraction with patients, health care practitioners, administrators,other systems, components, programs, and so forth.

A number of applications, publications, and external documents may beincorporated by reference herein. Any conflict or contradiction betweena statement in the body text of this specification and a statement inany of the incorporated documents is to be resolved in favor of thestatement in the body text.

Although described in the illustrative context of certain preferredembodiments and examples, it will be understood by those skilled in theart that the disclosure extends beyond the specifically describedembodiments to other alternative embodiments and/or uses and obviousmodifications and equivalents. Thus, it is intended that the scope ofthe claims which follow should not be limited by the particularembodiments described above.

What is claimed is:
 1. An accommodating connector configured to reduceblood clotting in a fluid flow between a medical device and a source offluid, the accommodating connector comprising: an outer connectingstructure configured to removably interlock with an outer portion of astandard medical connector to form an interior volume; a tube extendingthrough the outer connecting structure, an interior of the tube forminga fluid path and terminating at a port, the tube configured to extendfrom the accommodating connector and protrude into the interior volumein a direction aligned with the fluid path such that the fluid pathpasses through the interior volume, out of the port and continues in thesame direction into a lumen of the standard medical connector, theinterior of the tube aligned with the lumen and having a diameter thatis similar to a diameter of the lumen, thereby minimizing change in thecross-sectional area of the flow path from the accommodating connectorinto the standard medical connector to improve fluid flow; a lubriciouscoating configured to reduce blood clotting, the coating applied to atleast a portion of the fluid path within the tube; and a sealing mass onthe tube such that it encircles the tube, the sealing mass positioned ator near an interface between the port and the standard medical connectorand that has a shape configured to correspond with a shape of thestandard medical connector when the standard medical is removablyinterlocked with the accommodating connector such that the sealing massprevents the fluid from leaking out of the port and into the interiorvolume instead of proceeding into the lumen of the standard medicalconnector, the sealing mass configured to provide a seal only when theouter connecting structure of the accommodating connector is interlockedwith the standard medical connector such that the tube protrudes intothe interior space, the sealing mass thereby positioned and shaped tofunction together with the lubricious coating, the tube, and the tube'salignment with and similar diameter to the lumen of the medicalconnector to reduce blood clotting and confine the fluid flow to thefluid path while inhibiting leakage into and clotting within theinterior volume outside the fluid path.
 2. The accommodating connectorof claim 1, wherein the sealing mass has a shape configured tocorrespond with a shape of the standard medical connector such that thesealing mass shape generally approximates the shape of an opening in thestandard medical connector even when the accommodating connector is notmating with the standard medical connector.
 3. The accommodatingconnector of claim 1, wherein at least a portion of the sealing mass hasa generally frustoconical shape.
 4. The accommodating connector of claim1, wherein the sealing mass is made from a resilient or compressiblematerial.
 5. The accommodating connector of claim 1, wherein the sealingmass is made from silicone.
 6. The accommodating connector of claim 1,wherein the lubricious coating is applied to at least a portion of thesealing mass.
 7. The accommodating connector of claim 1, wherein thelubricious coating is applied to a surface that is located near aninterface between the port and the standard medical connector.